Apoptosis Reference Genome Targets (Archived): Difference between revisions

Revision as of 12:13, 1 March 2011

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]

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 th 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]

Range of species in which the pathway is found

Intrinsic apoptosis is thought to be present in multi-cellular organisms.

Apoptosis Experts

Ontology status

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

Families to annotate (BATCH 1)

BCL family Proteins

1. PTHR11256:SF8 BCL-2 HOMOLOGOUS ANTAGONIST/KILLER (BAK) (PRO-APOPTOTIC) Gallus gallus: Q5F404 Homo sapiens: Q16611 (BHF Priority, low: annotation incomplete) Mus musculus: MGI=MGI=1097161|UniProtKB=O08734 Rattus norvegicus: RGD=621635|UniProtKB=Q9JK59

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

Danio rerio:

ZFIN=ZDB-GENE-040426-1346|UniProtKB=Q7T381

ZFIN=ZDB-GENE-040801-131|UniProtKB=Q6DC66

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

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

Homo sapiens:

Q92934 (BHF-UCL priority; low. Annotation not complete)

Mus musculus:

MGI=1096330|UniProtKB=Q61337

Rattus norvegicus:

RGD=620103|UniProtKB=O35147

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)

Mus musculus

MGI=108093|UniProtKB=P70444

Rattus norvegicus RGD=620160|UniProtKB=Q9JLT6

5. 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

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)

6. PTHR11256:SF3 (Buffy, Debcl BCL-2 RELATED) Drosophila melanogaster FB=FBgn0029131|UniProtKB=Q7KM33 FB=FBgn0040491|UniProtKB=Q9NGX3

7. 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

8. Reaper; Q24475 Drosophila; matches no Panther family

9. HID; Q24106 Drosophila; matches no Panther family

10. GRIM; Q24570 Drosophila; matches no Panther family

11. Sickle; Q9VVP8 Drosophila; matches no Panther family

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

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

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

Proteins released from the mitochondrion to cytoplasm in response to apoptotic stimuli.

1. PTHR10266 (Cytochrome C)

Arabidopsis thaliana TAIR=locus=2164471|NCBI=NP_198897 TAIR=locus=2086553|NCBI=NP_189360

Caenorhabditis elegans WB=WBGene00000869|UniProtKB=Q18853

Danio rerio ZFIN=ZDB-GENE-031105-2|UniProtKB=Q3B7R0

Dictyostelium discoideum dictyBase=DDB_G0292594|UniProtKB=Q54D07

Drosophila melanogaster FB=FBgn0035600|UniProtKB=Q9VRL0 FB=FBgn0039651|UniProtKB=Q9VAM8

Homo sapiens P08574 (BHF Priority, low: annotation incomplete)

Mus musculus MGI=MGI=1913695|UniProtKB=Q9D0M3

Rattus norvegicus RGD=1306597|NCBI=XP_001072177

Saccharomyces cerevisiae SGD=S000005591|UniProtKB=P07143

Schizosaccharomyces pombe GeneDB_Spombe=SPBC29A3.18|UniProtKB=O59680

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 ZFIN=ZDB-GENE-070112-202|UniProtKB=A7E270

Gallus gallus ENTREZ=416860|NCBI=XP_415152

Homo sapiens Q9NR28 (BHF Priority, low: annotation incomplete)

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 1 Dictyostelium discoideum 1 Gallus gallus 1 Homo sapiens 2 P55008 (AIF1) (BHF Priority, low: annotation incomplete) Q9BQI0 (IBA2) Mus musculus 2 Rattus norvegicus 2