Apoptosis Reference Genome Targets

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Project leaders

UniProtKB GOA team, Emily Dimmer

Justification (Impact and significance)

Apoptosis is a programmed form of cell death involving the degradation of cellular constituents by a group of cysteine proteases called caspases. The caspases can be activated through either the intrinsic (mitochondrial mediated) or extrinsic (death receptor mediated) apoptotic pathways.

The intrinsic apoptotic pathway is characterized by permeabilisation of the mitochondria and release of cytochrome c into the cytoplasm. Cytochrome c then forms a multi-protein complex known as the ‘apoptosome’ and initiates activation of the caspase cascade through caspase 9.

The intrinsic apoptotic pathway has been chosen for a Reference Genome project as the curation work will complement and inform a planned apoptosis content meeting scheduled for June the 1st, assisted by domain experts from the Apo-Sys Consortium. In addition, as the intrinsic apoptotic pathway seems to have evolved at the same time as multicellular organisms, whereas the extrinsic pathway is a more recent evolutionary development in veterbrates, it is felt the intrinsic mechanism was more suited to a multi-organism curation project.

In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in an extensive variety of diseases. Excessive apoptosis causes atrophy, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. [1],[2]

While the importance of apoptosis in metazoans for development and maintenance has long been recognized, data from single-celled organisms have suggested that apoptotic pathways have ancient origins [10]

Notes for curators

Although the presence of active caspases and DNA fragmentation is helpful in identifying possible apoptosis, they should not be employed as an exclusive means to demonstrate this process as apototic cell death can occur without DNA fragmentation or caspase activity.[1]

Cell death is frequently considered to be ‘caspase-dependent’ when it is suppressed by broad-spectrum caspase inhibitors such as N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk). As a word of caution, however, it should be noted that Z-VAD-fmk does not act on all caspases with an equal efficiency, and it also inhibits calpains and cathepsins, especially at high concentrations (>10 μM). Moreover, Z-VAD-fmk has been associated with several off-target effects that would result from the binding to cysteines on proteins other than cysteine proteases[1]

Apo.png from Apoptosis. 2010 Mar;15(3):331-49.The zebrafish as a model organism for the study of apoptosis. Eimon PM, Ashkenazi A.

What to do if your target has no Panther family

Paul T has suggested it may be possible to add in (manually) any homologous genes that may have diverged too much to be recognized by the existing PANTHER HMMs. Panther did this for a C. elegans ortholog of p53 (though this revised family has not been released yet). Therefore if curators find any literature about the family history of these genes, it would be helpful if they could be flagged to be sent to Panther as they then can store the evidence for homology.

Range of species in which the pathway is found

Intrinsic apoptosis is thought to be present in all eukaryotes

Homologs of some apoptotic enzymes are found among the Bacteria, but not the Archaea [11].

Apoptosis Experts

Reactome (Mark Gillespie and Lisa Matthews) would like to hear feedback from the vertebrate groups on their representation of apoptosis

APO-SYS [1]

Ontology status

see also: http://wiki.geneontology.org/index.php/Apoptosis

Time frame of the project

Background reading

[1] [Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G; Nomenclature Committee on Cell Death 2009.Cell Death Differ. 2009 Jan;16(1):3-11. Epub 2008 Oct 10. http://www.ncbi.nlm.nih.gov/pubmed/18846107]

Highly recommended to read before starting curation; contains definitions of different types of cell death (apoptosis/necrosis/autophagic cell death/cornification, as described by the Nomenclature Committee on Cell Death.

[2] http://en.wikipedia.org/wiki/Apoptosis

[3] Molecular mechanisms of caspase regulation during apoptosis, Nature Reviews Molecular Cell Biology 5, 897-907 (November 2004) | doi:10.1038/nrm1496

[4] APOPTOSIS PATHWAYS AND DRUG TARGETS POSTER: John C. Reed and Ziwei Huang: http://www.nature.com/reviews/poster/apoptosis/index.html

[5] Apoptotic cell death "Nixed" by an ER-mitochondrial necrotic pathway.Kitsis RN, Molkentin JD. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9031-2. Epub 2010 May 6.

[6] The zebrafish as a model organism for the study of apoptosis. Eimon PM, Ashkenazi A.Apoptosis. 2010 Mar;15(3):331-49. good species comparison paper

[7]Apoptosis in yeast - mechanisms and benefits to a unicellular organism. Gourlay, C.W, Du, W. and Ayscough, K.R. Molecular Microbiology 2006 62 p.1515-1521.

[8] Regulation of DNA fragmentation: the role of caspases and phosphorylation. PMID:21182594 has nice diagram of phosphorylation regulating activity of caspases

[9]

[10]

[11] Koonin EV, Aravaind L. (2002) Origin and evolution of eukaryotic apoptosis: the bacterial connection. Cell Death Differ. 2002 Apr;9(4):394-404. http://www.ncbi.nlm.nih.gov/pubmed/11965492

Families to annotate

Number of Gene Products assigned per RefGen species

Gallus gallus: 22 targets

H. sapiens: 28 targets

Mus Musculus: 37 targets

Rattus norvegicus: 40 targets

Danio rerio: 50 targets

C. elegans: 12 targets

Drosophila Melanogaster: 19 targets

Arabidopsis thaliana: 25 targets

Dictyostelium discoideum: 4 targets

Saccharomyces cerevisiae: 5 targets

Schizosaccharomyces pombe: 4 targets


BCL family Proteins

Notes: many Bcl-2 family members also have a role in the cell cycle, see: PMID: 17303468

1. PTHR11256:SF8 BCL-2 HOMOLOGOUS ANTAGONIST/KILLER (BAK) (PRO-APOPTOTIC)

Gallus gallus:

Q5F404

Homo sapiens:

Q16611 (BHF Priority, low: annotation incomplete) Reactome Link

Mus musculus:

MGI=MGI=1097161|UniProtKB=O08734

Rattus norvegicus:

RGD=621635|UniProtKB=Q9JK59 - done


2. PTHR11256:SF4 APOPTOSIS REGULATOR (BOK) (PRO-APOPTOTIC)

Danio rerio:

ZFIN=ZDB-GENE-040426-1346|UniProtKB=Q7T381 - DONE 3/8/11

ZFIN=ZDB-GENE-040801-131|UniProtKB=Q6DC66 - DONE 3/8/11

Gallus gallus:

UniProtKB=Q9I8I2

Homo sapiens:

UniProtKB=Q9UMX3 (BHF Priority, low: annotation incomplete)

Mus musculus:

MGI=1858494|UniProtKB=O35425

Rattus norvegicus:

RGD=70984|UniProtKB=Q792S6 - done


3. PTHR16615 FAMILY NOT NAMED (BAD) anti-apoptotic

HUMAN FUNCTION FROM UNIPROT ENTRY:

Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 By similarity. Appears to act as a link between growth factor receptor signaling and the apoptotic pathways.

Danio rerio:

ZFIN=ZDB-GENE-000616-1|UniProtKB=Q4V925 - DONE 3/10/11

Homo sapiens:

Q92934 (BHF-UCL priority; low; KRUK Priority: Annotation not complete)

Reactome Link

Mus musculus:

MGI=1096330|UniProtKB=Q61337

Rattus norvegicus:

RGD=620103|UniProtKB=O35147 - done

4. PTHR15165 FAMILY NOT NAMED (BID). BH-3-only protein

HUMAN FUNCTION FROM UNIPROT ENTRY:

The major proteolytic product p15 BID allows the release of cytochrome c By similarity. Isoform 1, isoform 2 and isoform 4 induce ICE-like proteases and apoptosis. Isoform 3 does not induce apoptosis. Counters the protective effect of Bcl-2. Forms heterodimers either with the pro-apoptotic protein BAX or the anti-apoptotic protein Bcl-2 By similarity. p15 BID interacts with ITCH. (enables cross-talk between intrinsic and extrinsic pathways)


Gallus gallus:

UniProtKB=Q8JGM8

Homo sapiens:

P55957 (BHF Priority, low: annotation incomplete) Reactome Link

Mus musculus:

MGI=108093|UniProtKB=P70444

Rattus norvegicus:

RGD=620160|UniProtKB=Q9JLT6 - done

5. PTHR14299 (FAMILY NOT NAMED) PMAIP1

FROM HUMAN UNIPROT ENTRY:

Promotes activation of caspases and apoptosis. Promotes mitochondrial membrane changes and efflux of apoptogenic proteins from the mitochondria. Contributes to TP53/p53-dependent apoptosis after radiation exposure. Promotes proteasomal degradation of MCL1. Competes with BAK1 for binding to MCL1 and can displace BAK1 from its binding site on MCL1 By similarity. Competes with BIM/BCL2L11 for binding to MCL1 and can displace BIM/BCL2L11 from its binding site on MCL1. Interacts with MCL1 and BAX.

Danio rerio:

ZFIN=ZDB-GENE-070119-3|UniProtKB=Q0GKC8 - DONE 3/8/11

Gallus gallus:

ENTREZ=770077|NCBI=XP_001233390

Homo sapiens:

ENSEMBL=ENSG00000141682|UniProtKB=Q13794 (KRUK Priority) Reactome Link

Mus musculus:

MGI=1930146|UniProtKB=Q9JM54

Rattus norvegicus:

RGD=1359266|UniProtKB=Q5U777

6. PTHR15186 FAMILY NOT NAMED (BNIP3)

HUMAN FUNCTION FROM UNIPROT ENTRY:

Apoptosis-inducing protein that, which can overcome BCL2 suppression. May play a role in repartitioning calcium between the two major intracellular calcium stores in association with BCL2.

Might provide distinguishing information on involvement in programmed necrosis, as Nix/Bnip3L seems to be capable of inducing apoptotic and necrotic death programs, depending on whether it is located at the OMM or ER membrane.[5]

Caenorhabditis elegans:

WB=WBGene00015776|UniProtKB=Q09969

Danio rerio:

ZFIN=ZDB-GENE-051113-212|UniProtKB=Q32PK3 - DONE 3/8/11

ZFIN=ZDB-GENE-040325-1|UniProtKB=Q801Y7 - DONE 3/8/11

ZFIN=ZDB-GENE-050703-8|UniProtKB=Q801Y5 - DONE 3/8/11

ZFIN=ZDB-GENE-030131-8060|UniProtKB=Q5VK50 - DONE 3/8/11

ZFIN=ZDB-GENE-030131-2283|UniProtKB=Q5VK49 - DONE 3/8/11

Gallus gallus:

ENTREZ=419522|UniProtKB=Q5ZLK0

ENTREZ=423971|NCBI=XP_421829

Homo sapiens:

Q12983 BNIP3/NIX (BHF Priority, low: annotation incomplete)

O60238 BNIP3L (BHF Priority, low: annotation incomplete)

Mus musculus:

MGI=MGI=3646742|NCBI=XP_894501

MGI=MGI=3647611|NCBI=XP_001478238

MGI=MGI=3642435|NCBI=XP_001480489

MGI=MGI=109326|UniProtKB=O55003

MGI=MGI=1332659|UniProtKB=Q9Z2F7


Rattus norvegicus:

RGD=1565371|NCBI=XP_001063205 - pseudogene

RAT|RGD=1562663|NCBI=XP_573895 - gene record withdrawn

RAT|RGD=1565720|NCBI=XP_576259 - gene record withdrawn

RAT|RGD=621354|UniProtKB=Q66HQ4

RGD=620800|UniProtKB=Q9ET45


7. PTHR11256:SF3 (Buffy, Debcl BCL-2 RELATED)

Drosophila melanogaster:

FB=FBgn0029131|UniProtKB=Q7KM33

FB=FBgn0040491|UniProtKB=Q9NGX3


8. PTHR11256:SF19 (APOPTOSIS REGULATOR CED-9. BCL-2 RELATED)

C.Elegans UniProt Function:

Plays a major role in programmed cell death (PCD, apoptosis). Egl-1 binds to and directly inhibits the activity of ced-9, releasing the cell death activator ced-4 from a ced-9/ced-4 containing protein complex and allowing ced-4 to activate the cell-killing caspase ced-3.

Caenorhabditis elegans:

WB=WBGene00000423|UniProtKB=P41958

9. Reaper; Q24475 Drosophila; matches no Panther family

10. HID; Q24106 Drosophila; matches no Panther family

11. GRIM; Q24570 Drosophila; matches no Panther family

12. Sickle; Q9VVP8 Drosophila; matches no Panther family

13. EGL-1; O61667 C.elegans; matches no Panther family

14. CED-13; Q9TY06 C.elegans; matches no Panther family

15. CEP-1; Q20646 C.elegans; matches no Panther family


Apoptogenic factors released from the mitochondrion

1. PTHR11961 (FAMILY NOT NAMED) (Cytochrome C)

Arabidopsis thaliana:

TAIR=locus=2017729|NCBI=NP_173697

TAIR=locus=2140573|NCBI=NP_192742


Caenorhabditis elegans:

WB=WBGene00013854|UniProtKB=Q23240

WB=WBGene00017121|UniProtKB=P19974


Danio rerio:

ZFIN=ZDB-GENE-040625-38|UniProtKB=Q6IQM2

ENSEMBL=ENSDARG00000070841|ENSEMBL=ENSDARP00000095131 - REMOVED FROM ENSEMBLE Zv9, not remapped.

ZFIN=ZDB-GENE-060503-627|UniProtKB=Q1LW96 - DONE 3/10/11 I added this one (cycs) as it is the ortholog of the Human gene ENSG00000172115 in this cluster. Paul confirmed that it was absent from our gp2protein file at the last build of panther families..but will be present in next round.


Dictyostelium discoideum:

dictyBase=DDB_G0275537|UniProtKB=Q869N1

Drosophila melanogaster:

FB=FBgn0086907|UniProtKB=P04657

FB=FBgn0000409|UniProtKB=P84029

Gallus gallus:

ENTREZ=420624|UniProtKB=P67881

ENTREZ=770919|NCBI=XP_001234233

Homo sapiens:

ENSEMBL=ENSG00000188512|UniProtKB=A8MY23

ENSEMBL=ENSG00000172115|UniProtKB=P99999 (BHF Priority, low: annotation incomplete)

Reactome Link


Mus musculus:

MGI=88579|UniProtKB=P00015

MGI=88578|UniProtKB=P62897

MGI=3708587|NCBI=XP_001480451

MGI=3704493|NCBI=XP_001478445

MGI=3642431|NCBI=XP_001479464


Rattus norvegicus: 12


Saccharomyces cerevisiae:

SGD=S000000765|UniProtKB=P00045

SGD=S000003809|UniProtKB=P00044

Schizosaccharomyces pombe:

GeneDB_Spombe=SPCC191.07|UniProtKB=P00046


2. PTHR16491:SF0 (SMAC/DIABLO)

HUMAN FUNCTION FROM UNIPROT ENTRY:

Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). Interacts with NGFRAP1/BEX3. Interacts with BIRC2, BIRC3, XIAP and BIRC7.

Danio rerio:

ZFIN=ZDB-GENE-040426-1303|UniProtKB=Q7T3E1 - DONE 3/10/11

ZFIN=ZDB-GENE-070112-202|UniProtKB=A7E270 - DONE 3/10/11

Gallus gallus:

ENTREZ=416860|NCBI=XP_415152

Homo sapiens:

Q9NR28 (BHF Priority, low: annotation incomplete)

Reactome Link Reactome Link

Mus musculus:

MGI=MGI=1913843|UniProtKB=Q9JIQ3

Rattus norvegicus:

RGD=1310885|UniProtKB=Q5RK17


3. PTHR10356 (ALLOGRAFT INFLAMMATORY FACTOR-1, AIF1 )

HUMAN FUNCTION FROM UNIPROT ENTRY:

Apoptotic suppressor. Has E3 ubiquitin-protein ligase activity. HtrA2 can antagonize antiapoptotic activity by directly degrading th. Overexpression suppresses rpr and W-dependent cell death in the eye. Interaction of th with Nc is required to suppress Nc-mediated cell death; th-mediated ubiquitination of Nc. Interacts (via BIR 2 domain) with Nc (via residues 114-125). Rpr, W and grim can out compete Nc for binding th therefore removing th-mediated ubiquitination. Interacts (via BIR 2 domain) with HtrA2; this displaces any bound Nc

Danio rerio:

ZFIN=ZDB-GENE-030131-9646|UniProtKB=Q6PBZ5

Dictyostelium discoideum:

dictyBase=DDB_G0283533|UniProtKB=Q54QX0

Gallus gallus:

ENTREZ=417179|NCBI=XP_415461

Homo sapiens:

P55008 (AIF1) (BHF Priority, low: annotation incomplete)

Q9BQI0 (IBA2)


Mus musculus:

MGI=1919598|UniProtKB=Q9EQX4

MGI=1343098|UniProtKB=O70200

Rattus norvegicus:

RGD=61924|UniProtKB=P55007

RGD=1305081|NCBI=XP_001077954

4. PTHR22915:SF5 (APOPTOSIS-INDUCING FACTOR (AIF)-LIKE MITCHONDRION-ASSOCIATED INDUCER OF DEATH (P53-RESPONSIVE GENE 3) (AMID PROTEIN))

FROM YEAST UNIPROT ENTRY:

Putative FAD-dependent oxidoreductase involved in the resistance to cercosporin and other singlet oxygen-generating photosensitizers. Translocates from mitochondria to the nucleus under apoptotic conditions, where it degrades DNA and induces apoptosis

Arabidopsis thaliana:

TAIR=locus=504956456|NCBI=NP_680200

TAIR=locus=2081373|NCBI=NP_190005

Gallus gallus:

ENTREZ=423720|NCBI=XP_421597

Homo sapiens:

UniProtKB=Q9BRQ8 (BHF Priority; low)

Mus musculus:

MGI=1918611|UniProtKB=Q8BUE4

Rattus norvegicus:

RGD=1304964|NCBI=NP_001102004

Saccharomyces cerevisiae:

SGD=S000005357|UniProtKB=P52923

(An AIF orthologue regulates apoptosis in yeast.Wissing S et al. J Cell Biol. 2004 PMID: 15381687)


5. Apaf1 FAMILY NOT NAMED (PTHR22845)

HUMAN FUNCTION FROM UNIPROT ENTRY:

Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis. Monomer. Oligomerizes upon binding of cytochrome c and dATP. Oligomeric Apaf-1 and pro-caspase-9 bind to each other via their respective NH2-terminal CARD domains and consecutively mature caspase-9 is released from the complex. Pro-caspase-3 is recruited into the Apaf-1-pro-caspase-9 complex via interaction with pro-caspase-9. Interacts with APIP.

Danio rerio:

ZFIN=ZDB-GENE-000616-4|UniProtKB=Q9I9H8

Gallus gallus:

ENTREZ=417926|NCBI=XP_416167

Homo sapiens:

O14727 (BHF Priority, low: annotation incomplete)

Reactome Link

Mus musculus:

MGI=1306796|UniProtKB=O88879

Rattus norvegicus:

RGD=620575|UniProtKB=Q9EPV5

6. C. Elegans Ced-4 (P30429) possible functional ortholog of Apaf1, however no Panther family match.

C. elegans:

ced-4=WBGene00000418=C35D10.9

7. Drosophila Dark(Q7KLI1), similar to Apaf1, has no Panther family


Caspases

1. Metacaspases

from wikipedia: Metacaspases are related to caspases and paracaspase. The metacaspases are Arginine/Lysine-specific, in contrast to caspases, which are Aspartate-specific. Metacaspases are found in plants, fungi, and "protists," but not in slime mold or animals, In an analogous manner to caspases, metacaspases induce programmed cell death in both plants and fungi (yeast)

YEAST FUNCTION FROM UNIPROT ENTRY:

Mediates cell death (apoptosis) triggered by oxygen stress, salt stress or chronological aging. Regulated cell death can prevent a release of toxic cellular components, thus avoiding necrotic collapse of the colony, and can also provide nutrients for healthy cells. Therefore, regulated cell death in yeast colonies can be as important for their development as are apoptosis and related processes that occur within metazoa.

S.cerevisiae:

S000005723 (MCA1, YCA1)

S. pombe:

SPCC1840.04.

Arabidposis:

At1g02170 | UniProtKB:Q7XJE6 (metacaspase 1, AtMC1)

At4g25110 | UniProtKB:Q7XJE5 (metacaspase 2, AMC2)

At5g64240 | UniProtKB:Q9FMG1 (metacapase 3, AMC3)

At1g79340 | UniProtKB:O64517 (metacaspase 4, AMC4)

At1g79330 | UniProtKB:O64518 (metacaspase 5, AMC5)

At1g79320 | UniProtKB:O64519 (metacaspase 6, AMC6)

At1g79310 | UniProtKB:Q6XPT5 (metacaspase 7, AMC7)

At1g16420 | UniProtKB:Q9SA41 (metacaspase 9, AMC8)

(no Panther family available)

2. PTHR10454:SF30 (Caspase 3)

HUMAN FUNCTION FROM UNIPROT ENTRY:

Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin

Danio rerio:

ZFIN=ZDB-GENE-070607-1|UniProtKB=Q0PKX2

ZFIN=ZDB-GENE-011210-1|UniProtKB=Q98UI8


Gallus gallus:

UniProtKB=O93417

Homo sapiens:

P42574 (BHF Priority, low: KRUK Priority: annotation incomplete)

Mus musculus:

MGI=107739|UniProtKB=P70677

Rattus norvegicus: RGD=2275|UniProtKB=P55213

3. PTHR10454:SF31 (CASPASE-7)

Danio rerio: ZFIN=ZDB-GENE-050522-506|UniProtKB=Q503H4

Gallus gallus: ENTREZ=423901|NCBI=XP_421764

Homo sapiens:

P55210 (BHF Priority, low: annotation incomplete)

Reactome Link Reactome Link Reactome Link

=Mus musculus:

MGI=MGI=109383|UniProtKB=P97864

Rattus norvegicus:

RGD=620944|UniProtKB=O88550

4. PTHR10454:SF28 (DRICE)

DROSOPHILA FUNCTION FROM UNIPROT ENTRY:

Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 21 kDa (p21) and a 12 kDa (p12) subunit. Inactive pro-form can homodimerize. Nc and Ice can form a stable complex.

Drosophila melanogaster:

FB=FBgn0028381|UniProtKB=Q9VET9

FB=FBgn0019972|UniProtKB=O01382

FB=FBgn0010501|UniProtKB=O02002


5. PTHR10454:SF26 (CASPASE-8)

HUMAN FUNCTION FROM UNIPROT ENTRY:

Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.

Gallus gallus:

ENTREZ=395284|UniProtKB=Q90WU1

ENTREZ=693266|UniProtKB=Q4JQQ0

Homo sapiens:

Q14790 (BHF Priority, low: annotation incomplete)

Reactome Link

Mus musculus:

MGI=1261423|UniProtKB=O89110

Rattus norvegicus:

RGD=620945|UniProtKB=Q9JHX4

6. PTHR10454:SF25( Caspase 8)

Danio rerio:

ZFIN=ZDB-GENE-070608-1|UniProtKB=Q0PKX1 ZFIN=ZDB-GENE-000713-1|UniProtKB=Q9I8J3


7. PTHR10454:SF19 (CASPASE-9)

HUMAN FUNCTION FROM UNIPROT ENTRY:

Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.

Homo sapiens:

P55211 (BHF Priority, low: annotation incomplete)

Reactome Link

Mus musculus:

MGI=1277950|NCBI=NP_056548

Rattus norvegicus:

RGD=61867|UniProtKB=Q9JHK1

RGD=69064|UniProtKB=Q9JHK1

8. PTHR10454:SF38(Caspase -9)

Danio rerio:

ZFIN=ZDB-GENE-030825-5|UniProtKB=Q5U3Q7


9.PTHR10454:SF69 (CASPASE NC (DRONC))

DROSOPHILA FUNCTION FROM UNIPROT ENTRY:

Involved in the activation cascade of caspases responsible for apoptosis execution. Effector of steroid-mediated apoptosis during insect metamorphosis. Overexpression promotes programmed cell death. Interaction with th is required to suppress Nc-mediated cell death; via th-mediated ubiquitination of Nc. Rate-limiting caspase in rpr and W death pathway Interacts with th; residues 114-125 interact with the second BIR domain of th. Can form a stable complex with Ice. Rpr can out-compete Nc for binding th, therefore removing th-mediated ubiquitination.

Drosophila melanogaster:

FB=FBgn0026404|UniProtKB=Q9XYF4

10. PTHR10454:SF22 (CASPASE-8 DREDD)

Drosophila melanogaster:

FB=FBgn0020381|UniProtKB=Q8IRY7

11. PTHR10454:SF53 (Ced3 may be functional ortholog of vertebrate caspase -9)

C.ELEGANS FUNCTION FROM UNIPROT ENTRY:

Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP). Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.

Caenorhabditis elegans:

WB=WBGene00000417|UniProtKB=P42573

WB=WBGene00000819|UniProtKB=O18203

Inhibitors of Apoptosis (IAPs) and their regulators

1. PTHR10044

IAP family of proteins can potentially inhibit the enzymatic activity of live caspases and permanently remove capases through the ubiquitylation-mediated proteasome pathway.


Arabidopsis thaliana: TAIR=locus=2131571|NCBI=NP_195233

TAIR=locus=2012453|NCBI=NP_564945

TAIR=locus=2062374|NCBI=NP_181076

TAIR=locus=2014089|NCBI=NP_564052

TAIR=locus=2139310|NCBI=NP_192209

TAIR=locus=2207385|NCBI=NP_565200

TAIR=locus=2153227|NCBI=NP_851134

TAIR=locus=2133990|NCBI=NP_193705

TAIR=locus=2019983|NCBI=NP_172535

TAIR=locus=2036596|NCBI=NP_176260

TAIR=locus=2031471|NCBI=NP_177535

TAIR=locus=2033765|NCBI=NP_174531

TAIR=locus=2171042|NCBI=NP_199516

TAIR=locus=2063917|NCBI=NP_181511

Caenorhabditis elegans: WB=WBGene00000250|UniProtKB=Q18727

WB=WBGene00000249|UniProtKB=Q22837


Danio rerio: ZFIN=ZDB-GENE-030825-7|UniProtKB=Q7SXU1

ZFIN=ZDB-GENE-030826-2|UniProtKB=Q90WU8

ZFIN=ZDB-GENE-030825-6|UniProtKB=Q6ZM93

ZFIN=ZDB-GENE-030826-1|UniProtKB=Q90WU9

ENSEMBL=ENSDARG00000058082|ENSEMBL=ENSDARP00000075338

Dictyostelium discoideum: dictyBase=DDB_G0268864|UniProtKB=Q55EJ5

dictyBase=DDB_G0269184|UniProtKB=Q94491


Drosophila melanogaster: FB=FBgn0003691|UniProtKB=Q24306

FB=FBgn0015247|UniProtKB=Q24307

FB=FBgn0037808|UniProtKB=Q9VH01

FB=FBgn0038489|UniProtKB=Q9VEM2

FB=FBgn0034738|UniProtKB=Q8SWW8


Gallus gallus:

ENTREZ=374012|UniProtKB=Q90660

ENTREZ=374078|UniProtKB=Q9DDK0

ENTREZ=395280|UniProtKB=Q8UVF8

ENTREZ=768589|NCBI=XP_001231345

ENTREZ=421463|NCBI=XP_419512

ENTREZ=419239|NCBI=XP_417413

Homo sapiens: O15392 (BIRC5) Reactome Link

Q9NR09

Q96CA5

Q96P09 (BHF Priority, low: annotation incomplete)

Q13075

Q13490 (BIRC2)(BHF Priority, low: annotation incomplete)Reactome Link

Q13489 (BHF Priority, low: KRUK Priority annotation incomplete)

Q9NPP4 (BHF Priority, low: annotation incomplete)

P98170 (XIAP)(BHF Priority, low: annotation incomplete) Reactome Link

Mus musculus:

MGI=1203517|UniProtKB=O70201

MGI=1197009|UniProtKB=Q62210

MGI=MGI=1197007|UniProtKB=O08863

MGI=MGI=1298226|UniProtKB=Q9QUK4

MGI=MGI=1298220|UniProtKB=Q9R016

MGI=MGI=1298222|UniProtKB=Q9JIB6

MGI=MGI=107572|UniProtKB=Q60989

MGI=MGI=2676458|UniProtKB=A2AWP0

MGI=MGI=1858256|NCBI=NP_067520

MGI=MGI=3036243|NCBI=NP_001028539

MGI=MGI=1298223|UniProtKB=Q9QWK5

MGI=MGI=1276108|NCBI=NP_031592

Rattus norvegicus:

RGD=70499|UniProtKB=Q9JHY7

RGD=620692|UniProtKB=Q9R0I6

RGD=620690|UniProtKB=Q6P6S1

RGD=1307247|NCBI=XP_233842

RGD=1559914|NCBI=XP_226743

RGD=1562883|NCBI=XP_238302

RGD=621281|UniProtKB=Q8R4U8

RGD=621282|UniProtKB=Q9ESE9

RGD=1309831|NCBI=XP_001065561


Schizosaccharomyces pombe:

GeneDB_Spombe=SPCC962.02c|UniProtKB=O14064

2. PTHR22939:SF12 (SERINE PROTEASE HTRA2)

HUMAN FUNCTION FROM UNIPROT ENTRY: Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes or induces cell death either by direct binding to and inhibition of BIRC proteins (also called inhibitor of apoptosis proteins, IAPs), leading to an increase in caspase activity, or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves THAP5 and promotes its degradation during apoptosis. Isoform 2 seems to be proteolytically inactive. Cleavage of non-polar aliphatic amino-acids at the P1 position, with a preference for Val, Ile and Met. At the P2 and P3 positions, Arg is selected most strongly with a secondary preference for other hydrophilic residues.

Danio rerio:

25

Gallus gallus:

ENTREZ=395990|NCBI=XP_423666

Homo sapiens:

O43464 (BHF Priority, low: annotation incomplete)

Mus musculus:

MGI=1928676|UniProtKB=Q9JIY5

Rattus norvegicus:

RGD=1308906|NCBI=XP_001066414


3. PTHR22939:SF15(SUBFAMILY NOT NAMED) Pro-apoptotic serine protease NMA111

Arabidopsis thaliana:

TAIR=locus=2099619|NCBI=NP_566204

Saccharomyces cerevisiae

SGD=S000005067|UniProtKB=P53920, A6ZRW1


Schizosaccharomyces pombe

GeneDB_Spombe=SPAC23G3.12c|UniProtKB=Q9P7S1





Other possible targets

BAG family molecular chaperone regulators (Bcl-2 family)

ER Stress Response/Unfolded Protein Response

Defender against death DAD protein DAD1 or OST2

Arabidopsis thaliana: At1g32210

At2g35520

Saccharomyces cerevisiae: S000005629

Schizosaccharomyces pombe SPAC6F6.05

"Caenorhabditis elegans:" WBGene00000896

Drosophila melanogaster: FBgn0032035

Dictyostelium discoideum: DDB_G0291049

Danio rerio: ZDB-GENE-060503-233 | UniProtKB=A7E2L0

Gallus gallus: UniProtKB=O13113

Homo sapiens: UniProtKB=P61803

Mus musculus: MGI:101912 | UniProtKB=P61804

Rattus norvegicus: RGD:621028

Suggested from Reactome:

Q96FJ2 DYNLL2

P48454 PPP3CC

P63167 DYNLL1

P31749 AKT1

O43521 BCL2L11

Q9BXH1 BBC3

Q07817 BCL2L1

Q96LC9 BMF

P10144 GZMB

P30419 NMT1

P45983 MAPK8

P63098 PPP3R1

P31946 YWHAB

PDS5 Pdx1 PERK TRAF2 Ire1 Caspase4 CHOP ATF4

GO ontology developments

* When making term requests please prefix the SF summary field with 'APO', so that the GO editors can identify terms that are generated as a result of the work from the RefGen annotation project and content meeting.


* Bcl-2 Protein Complexes

https://sourceforge.net/tracker/index.php?func=detail&aid=1436494&group_id=36855&atid=440764

I've only given these terms a protein complex parent. Sandra wrote: "As to location - the Bax and Bak oligomers certainly seem to be associated with the mitochondrial membrane but its less clear for all the others." The review paper that Sandra refers to is from 2003. May be worth searching the more recent literature to see if we should give all or some of these complexes the additional is_a parent GO:0044455 mitochondrial membrane part, or any other appropriate parent. [Paola]



- rename GO:0006915 apoptosis as apoptopic process

  • Definition: A form of programmed cell death that begins when a cell receives internal or external signals that trigger the activity of proteolytic caspases, proceeds through a series of characteristic stages typically including rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), and plasma membrane blebbing (but maintenance of its integrity until the final stages of the process), and ends with the death of the cell.
  • Discussion:
    • 1. apoptosis should be narrower than the definition we currently have in GO, i.e. apoptosis is generally considered as just the morphological changes, where as the above definition includes the upstream processes, stimulating apoptosis and the signaling pathway involved.
    • 2. We have 1597 manual experimental annotations to apoptosis or children (968 proteins), including gene products such as casp-2, casp-9, BID, BCL10, cytochrome c; some of which we are saying should be in the signaling pathway leading to apoptosis (and many others that appear to be well upstream of/unrelated to apoptosis, e.g. sonic hedgehog, PML, fgf8, Col4A3).
  • Proposal: Renaming 'apoptosis' as 'apoptopic process' would mean the original definition can be kept, and the annotations to this term would be valid.
  • Caution: if possible avoid using 'apoptosis' for new GO terms, perhaps use 'apoptopic morphology'?
  • [Ruth, Emily, Rachael, Yasmin]

- Ontology consistancy re other 'cell death' GO terms Will similar ontology structures/terms be created for other child terms of GO:0012501 programmed cell death?[Ruth] eg GO:0048102 autophagic cell death, PMID: 20973794 [2]


- apoptosis in response to...

  • apoptosis in response to hypoxia [Ruth PMID:20436456] [3]
  • apoptosis in response to cobalt ion [Ruth PMID:20436456] [4]

- new term: intrinsic apoptotic pathway



- new term: extrinsic apoptotic pathway



[Ruth] below, trying out some ideas, not convinced these work yet.

- new term 1: signal transduction involved in initiation of apoptosis

- new term 2: signal transduction involved in mitochondrial outer membrane permeabilization

  • GO:0006915 renamed apoptopic process
  • is a > new term 1: signal transduction involved in initiation of apoptosis
  • is a >> new term 2: signal transduction involved in mitochondrial outer membrane permeabilization
  • [Ruth] PMID: 21041309

- new term 3: mitochondrial outer membrane permeabilization [5]

  • Definition to include this concept: the release of apoptogenic proteins from the mitochondrial intermembrane space commits the cell to death, either by a caspase-dependent or -independent mechanism
  • Exact synonym: MOMP
  • Bax and Bak would be annotated with this term
  • Plus regulation terms for this new term.
  • [Ruth] PMID: 21041309

- new term 4:induction of mitochondrial outer membrane permeabilization

  • Definition to include: Increases the rate of induction of mitochondrial outer membrane permeabilization, often facilitated by a pro-apoptotic BCL-2 family member (Bax or Bak).
  • Bim, Bid, Bad, Bik, Bmf, Hrk, Puma, Noxa etc. would be annotated with this term
  • [Ruth] PMID: 21041309

- new MF term 5:Bax/Bak activator activity

    • Definition: Increases the activity of a pro-apoptotic BCL-2 family member (Bax or Bak) resulting in oligomerisation, pore complex formation and mitochondrial outer membrane permeabilization.
  • or is this equivalent/almost equivalent to GO:0001844 protein insertion into mitochondrial membrane involved in induction of apoptosis
    • definition: The process in which a protein is incorporated into a mitochondrial membrane, contributing to the induction of apoptosis.
  • Bim, Bid, Bad, Bik, Bmf, Hrk, Puma, Noxa etc. would be annotated with this term
  • [Ruth] PMID: 21041309, Bid P70444 IDA PMID 10950869

- new ontology including new terms 3, 4, and 5

  • GO:0006915 renamed apoptopic process
  • > is a child new term 3: mitochondrial outer membrane permeabilization
  • >> is a pos reg child GO:0090200 positive regulation of release of cytochrome c from mitochondria
  • >>> is a child new term 4: induction of mitochondrial outer membrane permeabilization
  • >>>> part of child new MF term 5:Bax/Bak activator activity
  • GO:0006915 renamed apoptopic process
  • > is a child new term 4: induction of mitochondrial outer membrane permeabilization
  • Synonym: induction of cytochrome c release from mitochondria
  • [Ruth] PMID: 21041309
  • GO:0006915 renamed apoptopic process
  • > is a child new term 3: mitochondrial outer membrane permeabilization
  • >> is a pos reg child (is that right?) new term 2: signal transduction involved in mitochondrial outer membrane permeabilization
  • GO:0046902 regulation of mitochondrial membrane permeability
  • > is a pos reg child GO:0090200 positive regulation of release of cytochrome c from mitochondria
  • >> is a child new term 4: induction of mitochondrial outer membrane permeabilization

- new MF term 6:Bax/Bak inhibitor activity

  • Definition: Decreases the activity of a pro-apoptotic BCL-2 family member (Bax or Bak); decreasing pore complex formation and decreasing mitochondrial outer membrane permeabilization.
  • MCL1 would be annotated with this term
  • GO:0043066 negative regulation of apoptosis
  • > part of new MF term 6:Bax/Bak inhibitor activity
  • [Ruth] PMID:21036904, BCL2 PMID:9219694

- new cc term 7: mitochondrial outer membrane pore complex

  • Definition: A protein complex inserted in the outer membranes of mitochondria and acts as a pore that can open transiently to allow release of cytochrome c from the mitochondria to the cytosol, and consequently trigger apoptosis.

GO:0046930 pore complex

  • > is a child new cc term 7: mitochondrial outer membrane pore complex
  • > is a child GO:0005757 mitochondrial permeability transition pore complex

GO:0031307 integral to mitochondrial outer membrane

  • > is a child new cc term 7: mitochondrial outer membrane pore complex
  • [Ruth] PMID: 10934477
  • [Rachael - response to Ruth's suggestions]

1. I think there needs to be a more specific term name for the definition that is suggested above, e.g. 'mitochondrial apoptosis-induced channel' (synonym 'MAC', PMID:17294079). The term 'mitochondrial outer membrane pore complex' (suggested def: A protein complex inserted in the outer membranes of mitochondria and acts as a pore that can open transiently to allow release of gases, liquids or solutes) should be a more general parent term to both the new term 'mitochondrial apoptosis-induced channel' and to the existing term GO:0005742 'mitochondrial outer membrane translocase complex'

2. Would it be worth having, for consistency, a new term 'mitochondrial inner membrane pore complex' to have as a parent for 'mitochondrial permeability transition pore complex'?

i.e.

GO:0046930 pore complex

  • > is a child new cc term: mitochondrial outer membrane pore complex
    • > is a child new term: mitochondrial apoptosis-induced channel
    • > is a child GO:0005742: mitochondrial outer membrane translocase complex
  • > is a child new cc term: mitochondrial inner membrane pore complex
    • > is a child GO:0005757: mitochondrial permeability transition pore complex

3. The existing pore terms have inconsistent parentage;

GO:0005742: mitochondrial outer membrane translocase complex

  • > part_of GO:0005741 mitochondrial outer membrane
  • > is_a GO:0043234 protein complex
  • > is_a GO:0044455 mitochondrial membrane part

whereas GO:0005757: mitochondrial permeability transition pore complex

  • > part_of GO:0005740 mitochondrial envelope
  • > is_a GO:0046930 pore complex.

It seems as though GO:0005742: mitochondrial outer membrane translocase complex should be is_a GO:0046930 pore complex also (see PMID:10579717) and GO:0005757: mitochondrial permeability transition pore complex should be part_of GO:0005743 mitochondrial inner membrane (or GO:0031305 integral to mitochondrial inner membrane).

4. GO:0046930 pore complex definition: Any small opening in a membrane that allows the passage of gases and/or liquids. - should this also include proteins/solutes as it's child GO:0005757: mitochondrial permeability transition pore complex allows passage of <1500MW solutes (PMID:17294079)?

5. GO:0005757: mitochondrial permeability transition pore complex definition: A protein complex that connects the inner and outer membranes of animal mitochondria and acts as a pore that can open transiently to allow free diffusion of solutes between the mitochondrial matrix and the cytosol. - This definition should be improved as it doesn't appear to be a 'transient' effect. According to PMID:17294079, the PTP is in the mitochondrial inner membrane and when it opens it causes depolarization and swelling of the matrix space resulting in rupture of the mitochondrial outer membrane and an unspecific spilling of intermembrane space proteins into the cytosol.

  • Questions for the experts:

1. Is it still unclear whether the PTP opening is part of the initiation of apoptosis or as a consequence of it?

2. Do you consider Bcl and/or BAX (others?) to be involved in regulating PTP opening?


- new BP term 8: release of cytochrome c from mitochondria independent of permeability transition

  • alternative name/synonym: release of cytochrome c from mitochondria via mitochondrial outer membrane pore complex
  • Definition: The process that is mediated by a mitochondrial outer membrane pore complex and results in the movement of cytochrome c from the mitochondrial intermembrane space into the cytosol, which is an early step in apoptosis and leads to caspase activation.
  • GO:0001836 release of cytochrome c from mitochondria
  • > is a child new BP term 8: release of cytochrome c from mitochondria via mitochondrial outer membrane pore complex
  • plus regulation terms
  • Note that mitochondrial swelling and rupture, which occurs via mitochondrial permeability transition pore complex will also release cytochrome c
  • [Ruth] PMID: 10950869

- Query GO:0001844 protein insertion into mitochondrial membrane involved in induction of apoptosis

  • definition: The process in which a protein is incorporated into a mitochondrial membrane, contributing to the induction of apoptosis.
  • Comment: Note that this term is intended to cover the insertion of pro-apoptotic proteins such as Bax or its homologs into mitochondrial membranes which occurs as an early step in the apoptotic program.
  • This term is associated with BAX, however, from the placement of this term in the ontology BAX should not be annotated to this term:
    • The parent term GO:0072655 establishment of protein localization in mitochondrion confirms that BAX is the target of this term. The comment here appears to have been misinterpreted.
  • Possible solution:
    • Rewrite comment: Note that this term is intended to cover the insertion of pro-apoptotic proteins, such as Bax or its homologs, into mitochondrial membranes which occurs as an early step in the apoptotic program. This term should not be associated with targets of this process, such as Bax and Bak.
    • remove this annotation from Bax
  • [Ruth]

Cell-Specific GO terms for apoptosis - what should the criteria for cell-specific apoptosis terms?

e.g. e.g. [GO:0045850] positive regulation of nurse cell apoptosis, [GO:2000108] positive regulation of leukocyte apoptosis, [GO:0043525] positive regulation of neuron apoptosis, [GO:2000271] positive regulation of fibroblast apoptosis

- some cells tend to use certain apoptotic regulators: Example:

  • ovarian cell apoptois involves BOK,which has a restricted expression profile in reproductive tissues PMID:9922095
  • trophoblast cell fate seems not to involve Bax or Bak - as these are found at consistently low levels, where as there is a placental-specific isoform of Mtd (MtdP) PMID:19095301.
  • Bcl-2 appears to differently regulate Ca2+ levels in different cells (PMID:14996496)

-PMID: 12209154; talks about BH3-only proteins in controlling apoptosis in different cell types.

- should cell or organ-specific apoptotic terms need to feed into any other cell or tissue specific development? At present no indication of the specificity of apoptosis in the existing terms is present in the definitions.

- would terms such as 'apoptosis involved in the development of brain', kidney etc. more helpful than citing cell type in specific apoptosis terms?

- What would be the benefit of having such terms in GO rather than in the annotation format?

Human curation groups (GOA, BHF-UCL)


  • should we have a new protein binding term to describe binding of anti-/pro-apoptotic Bcl-2 proteins? The binding between Bcl-2 proteins regulates apoptosis (see PMID:17629468, PMID: 9356461)), Although there is BH domain binding (GO:0051400: BH domain binding) and children, its not clear that experiments defining the protein interactions that this domain is always directly bound by Bcl-2 proteins

Emily

--- GO:0016505 apoptotic protease activator activity should we ensure that all terms mentionning caspases should include metacapases as well ? Emily


- terms exist such as 'induction of apoptosis by oxidative stress' (GO:0008631 ) as well as 'induction of apoptosis in response to chemical stimulus'GO:0031558 - shouldn't the name and def of these terms follow the same pattern? (Emily)


Yasmin: requested new apoptosis relating to involvement of Pax2 and Pax8 in apoptosis during kidney development in PMID 17314325

-new terms regulation of apoptosis in metanephric development


Discussion points copied from EBI confluence page

PMID:14996496, table 1 provides links to papers that describe subcellular location of many pro- and anti-apoptotic proteins.

COMMENTS, ITEMS FOR DISCUSSION

BCL2 proteins are described as 'crucial regulators of apoptosis' (PMID:15868100)and the intrinsic apoptosis pathway is initiated by the release of mitochondrial cytochrome c into the cytoplasm, which results in the activation of caspases (15102863) - help in generating a defintion for intrinsic apoptosis?

- should the term ['GO:0006919] activation of caspase activity' be a child of positive regulation of apoptosis or induction of apoptosis rather than directly to apoptosis? (emily)

- def of apoptosis includes requirement for caspases - is this correct? Rachael.

- does all activation of caspases require other proteins also involved in apoptosis - therefore shouldn't this term be a part of apoptosis?

- apoptosis has a signalling and also the actual dying of the cell - DNA fragmentation, blebbing etc. Shouldn't we have an apoptosis signalling pathway terms? Ruth.

- how to decide whether a protein is involved in '+ve reg of apoptosis or induction ([GO:0006917])?emily. Becky suggests induction= turning on only, where as +ve reg is both turning on, and increasing rate.

when looking at experimental data - often counting number of cells they've died and committed to apoptosis so how can we work out induction or positive regulation? Ruth

- related to emily's point directly above; should we capture the cell type in which the apototic genes are expressed and hence request new cell types if not already in cell type ontology? eg: periodontal ligament fibroblast in PMID17340152 responding to mechanical stress (yasmin). Requested new cell type at https://sourceforge.net/tracker/?func=detail&atid=925065&aid=3213704&group_id=76834

-GO:0016505 apoptotic protease activator activity; probably need a metacapase child term as well as a caspase term?

- in dying cells, hBok becomes firmly integrated into the mito membrane (whereas in healthy cells it is mainly located in the cytoplasm). How should htis be represented?

1. (Positive) regulation of mitochondrial permeability transition pore activity (or: activation of mitochondrial permeability transition pore)

is_a child of GO:0046902 regulation of mitochondrial membrane permeability may also need a has_part relation with 'apoptosis'

PMAIP1 (Q13794) may activate the permeability transition-related pore to release cytochrome c from mitochondria into cytosol. PMID:14500711

References for PT pore - PMIDs:10393078; 12728245

Need to look at this a bit more

Rachael's comments: It seems that the PT pore is not just apoptosis-specific; from PMID:17453156 'This complex has two functions: firstly, it regulates the integration of oxidative phosphorylation into the cellular energy household and secondly, it induces cell death when converted into an unspecific channel.', so it doesn't appear to be created by BAK, just activated - although I haven't read enough about this yet. Additionally, the authors go on to say that the PT pore may also be involved in cell death via necrosis, so we should be careful to not to think (and I know you weren't suggesting this) of this mechanism of mitochondrial permeability as apoptosis-specific.

Ruth's comments: I now appreciate the distinctions you were making here, the mitochondrial permeability transition pore complex crosses both mitochondrial membranes, and opening it leads to swelling of mitochondria. Whereas BAK pores lead to cytochrome c release and only target the outer membrane of mitochondria. I have no idea if BAK pores have any relationship with the mitochondrial permeability transition pore complex.

But it would be good to have a new term: mitochondrial outer membrane pore complex (have added to wiki).

However I am now fairly sure that BAK1 and probably BAX do actually form a pore:wikipedia: http://en.wikipedia.org/wiki/Apoptosis Bax and/or Bak form the pore, while Bcl-2, Bcl-xL or Mcl-1 inhibit its formation.PMID: 21036904: The proapoptotic effectors (BAX and BAK) contain three BH regions (BH1-3) and directly mediate mitochondrial outer membrane permeabilization, which leads to apoptosis..... BAK targets the outer membrane of mitochondria and endoplasmic reticulum through its C-terminal transmembrane (TM) helix (3,-,5). ... When apoptosis is induced ... BAK undergoes a conformational change, termed BAK activation, that is characterized by the insertion of additional ±-helical elements into the membrane and the assembly of BAK into higher order oligomers (10, 11).PMID: 10950869 (2000) Activated tBID results in an allosteric activation of BAK, inducing its intramembranous oligomerization into a proposed pore for cytochrome c efflux.PMID: 10934477 good summary of this too. Here we show that nanomolar BAX rapidly forms membrane pores12, 13 that release intravesicular carboxyfluorescein, fluorescein-isothiocyanate-conjugated dextran (FITC-dextran) or FITC-cytochrome c.

Will also have to go back and edit the BAX annotations I made years ago to mitochondrial permeability transition pore complex.

2. Intrinsic apoptotic pathway GO:NEW; extrinsic apoptotic pathway GO:NEW; NF-kappabeta apoptotic pathway (Yasmin)

is_a child of [GO:0006915] Apoptosis (BAD Q92934 PMID:17340152)

3. Induction of apoptosis by UV as is_a child of GO:0008624 induction of apoptosis by extracellular signals PMID: 15901672 Mouse BAK (O08734) mediates UV-induced death of fibroblasts.

4. Considering requesting Bax/Bak inhibitor activity IDA PMID: 21041309 (Ruth) (I (Rachael) agree, PMID:15901672 has IMP evidence for mouse Mcl1 P97287 and human Bcl-Xl Q07817-1 as inhibitors of BAK)

5. Could we have new term for the action of BH3-only proteins (e.g. Noxa, Puma, Bad, Bik etc. ) on prosurvival proteins (Bcl-2 related), i.e. the BH3-only proteins bind to and neutralize the pro-survival proteins. Maybe 'negative regulation of survival gene product activity'? PMID:15901672 PMAIP1 (Noxa) expression displaces Mouse Mcl1 (P97287) from Bak and triggers Mcl1 degradation. Already have GO:0045884 'regulation of survival gene product expression'.

Taxonomic Restrictions of GO terms

- limit extrinsic apoptotic pathway (GO:new) to vertebrata

Manual Annotation Concerns

Automatic Annotation Concerns