Of Apoptosomes and Oncogenes: Repurposing a Death Machine & Deconstructing the Action of P53 Mutations

It is now well appreciated that the apoptosome, which governs caspase-dependent cell death, also drives nonapoptotic caspase activation to remodel cells. However, determinants that specify whether the apoptosome acts to kill or remodel have yet to be identified. I show here that Tango7 genetically interacts with the apoptotic machinery but instead of regulating cell death, collaborates with the apoptosome to drive caspase-dependent cellular remodeling. Specifically, Tango7 is required for non-apoptotic caspase activity during spermatid remodeling and localizes to the active apoptosome compartment in these cells via its C terminus. Furthermore, Tango7 directly stimulates activity of reconstituted apoptosomes in vitro. These and other data presented here suggest that Tango7 physically recruits the apoptosome to specify this complex for nonapoptotic cellular remodeling. In vivo genetic model systems are powerful tools to deconstruct activity of genes driving human disease. The tumor suppressor p53 is mutated more than any other gene in human cancer, but unlike other tumor suppressors, it acquires missense mutations which encode oncogenic variants. These gain-of-function mutants promote more aggressive and metastatic cancers in vivo but their oncogenic activity is not well understood. To address this problem, I have exploited Drosophila as a platform to study and stratify human p53 (hp53) mutants. I replaced fly p53 with either wild-type hp53 or 5 of the most prevalent hp53 mutations in cancer. In this system, hp53 is under control of endogenous Dp53 regulatory elements and can regulate in vivo transcriptional activation and apoptosis like its fly counterpart. Furthermore, wild-type hp53 forms foci in the germline that localize to the same subnuclear compartment as Dp53 foci. This property is compromised in all of the gain-of-function mutants and can thus be used to distinguish oncogenic variants from wild-type hp53. Future studies aim at finding whether this and other properties shared among the 5 mutants can help stratify oncogenic p53 mutations found in human cancer.

Author dc:creator

• D'Brot, Alejandro

Contributors dc:contributor

• Scaglioni, Pier Paolo
• Shay, Jerry W.
• Yu, Hongtao

• Apoptosomes
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Caspases
• Drosophila melanogaster
• Drosophila Proteins

Language dc:language

en_US

Identifier

952355677

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/3311