Talk:Apoptosis

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Minutes of Apoptosis Content Meeting, June 1st 2011

Present: Paola Roncaglia, Becky Foulger, Jane Lomax, Emily Dimmer, Rachael Huntley, Susan Tweedie, Ruth Lovering, Gabriela Imreh, Carmela Dell'Aversana, Yuval Gilad, Luca Grieco, Rajiv Kumar, Marcus Chibucos (late afternoon only)

YG: Metacaspase and caspase have same function, so don’t need to distinguish between them at the function level

ED: Suggest having caspase activity and metacaspase activity as synonyms of cysteine-dependent protease activity. Are all caspases involved in apoptosis, definitively?

Experts: No

RL: could we have a new term, cysteine-dependent protease activity involved in apoptosis?

ED: This might be useful for distinguishing between proteins that are involved in apoptosis and those that are not. Would this be of benefit or should we have separate annotations and use Col. 16.

RL: Would be more consistent with the transcription overhaul

YG: Caspases have hundreds of targets, will have to make lots of new terms for processes involved in

JL: But would have no linkage between function and process

BF: Is the same caspase involved in different processes?

GI: Yes, function is the same but acts in different processes.

Other organism apoptosis term: JL: There is no problem with existing term, regulation of apoptosis in other organism Might have to tweak definition according to what you decide on the definition of apoptosis.

Definition of apoptosis: 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.

ED: Is the only difference between necrosis and apotosis differ on how the cell is cleared up?

GI: Yes, they look very different under microscope

RL: Death of the cell is what differs, blebbing etc. Not just clean up.

Mechanism is different, needs to be in definition.

RL: Apoptosis is referred to as the morphological changes, deterioration of the cell. We are covering too much in the definition, better to call it apoptotic process

BF: would fit better with signalling terms. How would you feel about having apoptosis limited to the morphological changes

YG: No, it includes the processes leading up to it. How would you define the end point – this is cell death

RL: but if you have neg. reg. of apoptosis, the cell doesn’t die

ED: would you include bcl2?

YG: Yes, maybe you could divide it into sub-processes of apotosis

RL: As long as you agree that all processes beginning with extracellular signalling, even if the cell doesn’t die, are included in apoptosis

YG: Yes, would agree with this.

BF: You would start the process with ligand binding?

YG: Yes

GI: I don’t think you can start with ligand binding or DNA damage as in many cases, the way the cell will die is part of the process. Sometimes it will be necrosis, sometimes apoptosis. E.g. if the signal was DNA damage, the cell has to decide how to die, caspase 8 was knocked out so it chose necrosis. Not happy with apoptosis definition starting with the signal.

RL: People talk about apoptotic process rather than apoptosis

BF: Could limit DNA fragmentation etc to apoptotic fragmentation phase

YG: end point is different, apoptosis, necrosis, autophagy. Very context dependent, several proteins can be involved in many processes so they can be attached to all of these.

Action item: Change ‘apoptosis’ term name to ‘apoptotic process’ Action item: Re-write definition of ‘apoptotic process’

BF: What are the types of non-programmed cell death.

YG: In non-programmed cell death there is no signalling

GI: ‘Mitotic catastrophe’ is a pre-phase, it is not a type of cell death. Should be removed.

ED: Not sure whether we should explicitly include the terms intrinsic or extrinsic pathways, maybe better as synonyms

YG: these are the terms that are used in the literature, so should be in them

RL: Could we have ‘initiation of apoptotic process’ as a child term?

YG: Not really as many things can initiate

ED: Fas receptor activation of cell death, is this outside of the apotosis process or part of it?

GI/YG: Fas receptor can result in apoptosis or necrosis

RL: Would have ‘Fas receptor signalling involved in apotosis’ and ‘Fas receptor signalling involved in necrosis’

GI: Apoptotic bodies are always present in apoptotic process, but DNA fragmentation (DNA ladder) is not necessarily always apoptosis.

Discussion on how to describe cell death within the definition of apoptosis process

RH: We already have cell death as a term

JL: Need to work on the definition of this term and then we can say ‘leads to cell death’ in the definition of apoptosis process.

Action Item: Work on the definition of cell death to include all types of cell death Action Item: Make ‘apoptotic body’ a cellular component

RL: Need to define programmed cell death in a similar way

BF: Do we want intrinsic and extrinsic pathway terms?

ED: Don’t like the terms induction of apoptosis by extracellular and intracellular signals.

GI: Intracellular signals – the signal is always coming from extracellular, one type of signal (extracellular) causes apoptosis directly by binding to receptor, the other goes indirectly via a pathway (currently intracellular).

Action item: Make new term: ‘apoptotic signaling pathway’ and child terms intrinsic and extrinsic apoptotic signaling pathway

GI: Don’t need p53 to induce cell death, so cannot say the signalling pathway starts with p53

JL: We can definitely say that extrinsic pathway starts with the death receptor, but it’s more difficult for the intrinsic pathway.

GI: Intrinsic pathway doesn’t only start with DNA damage, could be calcium levels, ER stress

BF: Could just say that it starts with reception of an intracellular signal, e.g. DNA damage, growth factor withdrawal etc.

ED: Can we have child terms of intrinsic apoptotic signaling pathway e.g. ‘intrinsic apoptotic signaling pathway by oxidative stress’

Action item: Remove term ‘induction of apoptosis by extracellular signals’ and move child terms (with some re-working) under ‘intrinsic apoptotic signalling pathway’

Action item: Change ‘induction of apoptosis by hormones’ to hormone-mediated signaling pathway

Breaking down individual apoptotic processes

Extrinsic pathway.

GI: Death receptors all have the death domain.

YG: There are many decoy receptors (we have decoy death receptor activity).

Action item: Make new term ‘death receptor agonist activity’ as a child of ‘receptor agonist activity’

Action item: Make new term ‘DISC assembly’ as a child of ‘apoptotic process’

Action item: Email Boris, what point does cross talk begin/end between intrinsic and extrinsic pathways

Action item: Make new term ‘Death-induced signaling complex’

Action item: Look into renaming of ‘activation of caspase activity’ to ‘activation of cysteine-type endopeptidase activity’

Caspase is activated by a cleavage event and then it’s activity is regulated by phosphorylation, so ‘activation of caspase activity by protein phosphorylation’ is actually a regulation

Action item: possibly obsolete ‘activation of caspase activity by protein phosphorylation’ unless we can find examples

GI: don’t like the wording activation of caspase activity, could have caspase activation instead

Action item: change ‘activation of caspase activity’ to ‘caspase activation involved in apoptotic process’

Regulation of mitochondrial membrane permeability – we have terms already

RH: Do BAX/Bcl2 regulate opening of PTP?

Action item: RH: Look up Boris lab papers for release of cytochrome c, MAC and PTP, email Boris lab with specific questions

Action item: Make new term ‘release of proteins from mitochondrial intermembrane space’

Action item: Email Boris lab. Mitochondrial pores – what is released? Does it depend on size of solutes or are certain molecules released?

Action item: Check annotation examples for the existing term ‘release of matrix enzymes from mitochondria’, if need to keep this, change term name to ‘release of protein from mitochondrial matrix’

Action item: Include in email to Boris lab: ‘mitochondrial fragmentation’ can we put as a morphological change of apoptosis instead of a sub-process of apoptotic process?

Definition of apoptosome: A multisubunit protein complex involved in the activation of apoptosis. In mammals it is typically composed of seven Apaf-1 subunits bound to cytochrome c and caspase-9. A similar complex to promote apoptosis is formed from homologous gene products in other eukaryotic organisms.

YG: The complex provides a platform to activate caspase 9

Action item: Contact yeast groups to check if yeast have apoptosomes Action item: GO:0071550 ‘death domain-mediated complex assembly’ appears to be redundant with new ‘DISC assembly’ term – merge terms

YG: c-FLIP – a homolog of caspase 8 prevents DISC assembly. Procaspase 8 and 10 are involved in DISC assembly

Action item: Bring up at an annotation call: ‘protein complex assembly’ and the role of the components in assembly

Action item: Revise use of ‘aggregation’ in protein complex terms

Next sub-process: Activation of effector caspases Initiator caspases activate effector caspases and effector caspases activate DNA degradation etc.

Action item: Make new term ‘effector caspase activation’. But need another way to describe effector and initiator caspases within GO

YG: the same caspases can be involved in developmental processes that are separate from cell death, e.g. erythropoeisis

BF: So is it correct to say that apoptosis execution process would start with actions of effector caspases and apoptotic signalling process would end with activation of effector caspases?

Experts: Yes, but only for caspase-dependent apoptosis

PR: Anti-apoptosis: Now have negative and positive regulation of anti-apoptosis. Can we remove anti-apoptosis term without losing information? We currently have 2000 annotations to anti-apoptosis

CD: would like to keep distinction between anti-apoptosis and neg. reg. of apoptosis. Some proteins have different functions based on interactions with other proteins, e.g. BAX is pro-apoptotic, if large quantities of Bcl2 are present then this function of BAX is suppressed.

RL: Is anti-apoptosis an active process or is it just negatively regulating apoptosis?

ED: anti-apoptotic factors can regulate transcription

MC: depends on the target. If you are interfering with binding, this is regulation; if you are destroying a protein, this is an anti-type of effect.

ED: Pro-apoptotic and anti-apoptotic seem to be a naming system for different types of proteins.

RL: positive regulation of anti-apoptosis annotations – Bcl2L1, transcription factos PAX4, SMAD7, ANGPT1

BF: Would be better to use regulation of sub-processes, e.g. regulation of apoptosome assembly, regulation of mitochondrial membrane permeability. Still not clear whether we need both anti-apoptosis and neg. reg. of apoptosis.

Experts: happy to have these sub-terms, even if they are under regulation of apoptosis

PR: keep anti-apoptosis as a synonym of negative regulation of apoptosis

Action item: Obsolete ‘anti-apoptosis’ and add in regulation terms for the sub-processes of apoptotic process under ‘regulation of apoptotic process’

ED: expression of survival genes

YG: not all survival genes are anti-apoptotic

BF: then ‘regulation of survival gene product expression’ is in the wrong place under ‘anti-apoptosis’.

Action item: move ‘negative regulation of survival gene product expression’ to under ‘positive regulation of apoptosis’ and move ‘positive regulation of survival gene product expression’ to under ‘negative regulation of apoptosis’

Action item: Obsolete ‘positive regulation of anti-apoptosis’ and ‘negative regulation of anti-apoptosis’

GO term ‘Phosphatidylserine exposure on apoptotic cell surface’

RL: This should be in the same place as DNA fragmentation

BF: What should we call the end point of apoptosis?

GI: ‘Execution phase of apoptosis’

Action item: make new term ‘execution phase of apoptosis’

Need an alternative name to caspase-independent apoptosis

YG: this is not apoptosis

GI: we need to consider this more, would be happy with apoptosis-like

Action item: consult apoptosis community on what to call apoptosis-like process that is independent of caspase

Need type I and type II apoptosis child terms for extrinsic apoptosis

Action item: make new terms ‘extrinsic apoptotic signaling pathway via apoptotic mitochondrial change’ and ‘extrinsic apoptotic signaling pathway via direct activation of effector caspase’ as child terms of ‘extrinsic apoptotic signaling pathway’

Minutes of apoptosis call, May 12th 2011

Present: Paola Roncaglia, Becky Foulger, Sam Kerrien, Yasmin Alam-Faruque, Rachael Huntley, Susan Tweedie, Ruth Lovering, MGI curators (Harold Drabkin, David Hill, Li Ni, Mary Dolan, Dmitri, Judy Blake), Adi Kimchi (Weizmann Inst. Israel), Oliver Kepp and Lorenzo Galluzzi (Institut Gustave Roussy, France), Gabriela Imreh and Boris Zhivotovsky (Karolinska Inst. Sweden).

Paola's presentation;

BZ: (On Definition of apoptosis slide) So you are not talking about apoptosis being a pathway?

PR: Need to define exactly where it begins and ends and what regulates it. Should we consider apoptosis as a pathway in itself.

BZ: Morphological changes don't lead to cell death they are as a result of cell death/apoptosis

DH: Yes we need to know what apoptosis is, are morphological changes part of apoptosis or as a result of apoptosis. Where does apoptosis end. We need experts opinion on this at the content meeting.

General discussion;

AK: Do you have a list of all genes that you think are relevant?

PR: We can point you to the gene list we are working on, but we first need to define the terms before we can annotate

SK: The annotation started a few weeks ago, but it became clear that the terms were lacking

BZ: Wants Paola’s presentation to look through before the meeting

BZ or Gabriela and Oliver (in place of Lorenzo) will try to make the June meeting. Adi will be at the meeting

RF: Are there any issues that you have come across that we should look at before June

AK: We will send you some things after going through the presentation

SK: Will send the presentation to the APO-SYS consortium to make them aware of the progress and allow them to give feedback

DH: think of processes in terms of what the gene targets do.

AK: i agree and this is important

DH: One outcome of the meeting would be to redesign GO to describe apoptosis but also a list of gene products that are involved in the apoptosis processes

PR: What would you include in the apoptosis term?

BZ: Will go through the presentation first and then comment

SK: Will send the presentation and a list of GO browsers to the experts

Action Items;

1. Sam send presentation to all experts and attendees of the call

2. Sam: need to look at minutes/ slides from last year’s Stockholm meeting as discussion are on internal website from the last meeting

3. Sam to send us names and affiliations of people present at call today

4. Sam to suggest GO browser tools: QuickGO/ AmiGO and send links

5. Send link of Apoptosis RG wiki link which lists genes involved in (Intrinsic) apoptosis.



Minutes of Apoptosis Call, July 20th 2011

Present:

  • Paola Roncaglia (GO)
  • Emily Dimmer (GOA)
  • Susan Tweedie (FlyBase)
  • Rebecca Foulger (GO)
  • Ruth Lovering (BHF-UCL)
  • David Hill (MGI)
  • Bijay Jassal (Reactome)
  • Simon Fourquet
  • Marcus Chibucos
  • Marc Gillespie (Reactome)
  • Luca Grieco
  • Brigitte Kahn-Perlès
  • Yuval Gilad
  • Sebastien Dazy


The slides referred to below are here File:Apoptosis call 20 07 2011.pdf.


SLIDE 5: DEFINITION OF CELL DEATH ; GO:0008219.

  • David Hill: Are there any cases where a membrane integrity is disrupted but a cell does not die? Perhaps in plants (eg phloem). David wants to check it's ok to have 'loss of membrane integrity' in definition.
    • A: Since we didn't know of any, the definition will be kept as suggested.


SLIDE 6: APOPTOTIC BODY

  • Q: In some cases, can the cell be phagocytosed before the appearance of apoptotic bodies? (if so, they won't always be present in apoptotic processes).

Marcus suggested a revision to the proposed definition:

FROM:
to become known as apoptotic bodies
TO:
to become apoptotic bodies.
  • Q: David Hill wonders if 'apoptotic body' belongs in the cell ontology, rather than GO component. We should ask Chris since it deviates from the way we use part_of in GO.


SLIDE 7: PROGRAMMED CELL DEATH ; GO:0012501

  • Agreed that PCD definition is ok.
  • Minor suggestion to change 'signaling pathways' to 'signaling pathway'.
  • David Hill: add HAS_PART relationship between generic signaling pathway term, and 'programmed cell death ; GO:0012501'.


SLIDE 8: CASPASE-INDEPENDENT CELL DEATH

  • Simon F: It's not very useful because it's a catch-all for anything that doesn't go via a caspase route. We shouldn't define terms based on the lack of a component.
  • Susan Tweedie: It's like the 'orphan receptor' terms that were dumping grounds. It's like a catch-all term.
  • David Hill: It's a problematic negative term. You absolutely know that caspases aren't used in the process, and if that's a true reflection of the process, then that's ok. But is this a real biological process, or an experimentally-induced (in vitro) process just done by looking at effects of caspase inhibitors.


SLIDE 9: MITOTIC CATASTROPHE

  • Paola: Doesn't fit under the apoptosis node because it can trigger cell death or senescence.
  • Becky and Emily: Is it a genuine process, or is it just mitosis-gone-wrong?
  • Susan: Most fly papers were describing what has gone wrong with mitosis.
  • David: Are we looking at the consequence of something gone wrong, or a true process? Are there gene products involved in mitotic catastrophe?
  • AI: REMOVE 'mitotic catastrophe ; GO:0070270' from GO.


SLIDE 15: SPLIT OF APOPTOTIC PROCESS

  • It was agreed that the split of apoptotic process (formerly apoptosis) into signaling steps and an execution phase, is the best way to go.


SLIDE 16: DEFINITION OF APOPTOTIC PROCESS ; GO:0006916.

  • David Hill: Q: Is 'typically' correct terminology in the definition?


SLIDE 17: DEFINITION OF APOPTOTIC SIGNALING PATHWAY ; GO:0039101

  • Definition approved.


SLIDES 18 & 19: EXTRINSIC AND INTRINSIC SIGNALING PATHWAYS

  • Definitions approved.
  • We have 'ends when the execution phase of apoptosis is triggered' to fit in with the signaling pathway terms which regulate a downstream cellular process. Marcus was originally concerned about this phrase, but understands the logic: i.e. we're not saying the signal doesn't continue on, but just that the signaling pathway itself ends.


SLIDE 21: EXECUTION PHASE OF APOPTOSIS

  • All agreed.


SLIDES 22-28:

  • Paola: the idea is to describe what is starting the process (e.g. oxidative stress)
  • Emily: PMID 20727425 shows that the granzyme B pathway and the extrinsic pathways are separate. So perhaps the granzyme pathway shouldn't be a child of extrinsic apoptosis?
  • David: It would be better to define the pathway rather than the chemical that activates the pathway.
  • Paola: We need a term for dependence receptor signaling.
  • Becky: PMID 15044679 has a nice definition:
dependence receptor signaling pathway ; GO:NEW
Signal transduction that is initiated by the withdrawal of ligands from specific receptors.


SLIDE 30: CASPASES

  • David Hill: We have process terms for 'regulation of caspase activity', which is problematic since we don't have caspase activity in the MF ontology. We're doing a dis-service to the community in not having caspase activity terms in GO.
    • One option: make a MF term (cysteine protease activity involved in apoptosis, broader synonym: caspase activity) that does NOT refer to a gene product, but rather a MF that's involved in apoptosis. We could distinguish between initiator caspases and effector caspases based on function/process links. i.e. create process terms:
initiation of apoptosis ; GO:NEW
execution of apoptopsis ; GO:NEW

and have function terms under these.