Visit our Expo - Redox and Inflammation signaling 2012

Live and let die by 73 - mechanisms of degradation and chemoresistance
Michael J. Pinkoski
MRC Toxicology Unit
Leicester, United Kingdom
p73 belongs to a family of transcription factors, including p53 and p63, that mediates
responses to DNA damage and cellular stress by inducing DNA repair, cell cycle arrest and
apoptosis. p73 is expressed as two isoforms, TA and DN, that have opposing biological
effects with DNp73 has a dominant negative/repressive effect on TAp73. Therefore, TA/DN
ratios dictate p73-dependent cellular responses to such insults as genotoxic chemotherapeutic
agents. In fact, DNp73 is associated with reduced survival in hepatocellular carcinoma (HCC)
patients and is therefore an indicator of a negative prognosis. Mechanistically, p73 is capable
of engaging both intrinsic and extrinsic apoptosis pathways. TAp73 induces transcription of
CD95 and increased sensitivity to CD95-induced apoptosis. TAp73 also induces expression of
PUMA, Noxa and Scotin to engage death pathways via the mitochondria and apoptosome.
Unlike p53, p73 mutations are rarely observed in human cancers, however, p73 activity is
influenced by protein stability. p73 protein degradation is regulated by the E3 ubiquitin ligase,
Itch, whereas stabilization of p73 protein is positively regulated by the nuclear body protein,
PML. Both TA and DNp73 proteins are degraded in an Itch dependent manner, but
interestingly, both Itch and DNp73 are downregulated following genotoxic stress.
Degradation of DNp73 under these conditions is not mediated by Itch. TAp73, is not
decreased following DNA damage, lending further support to the hypothesis TAp73 acts as a
tumour suppressor while DNp73, which can inhibit both TAp73 and p53 would represent an
oncogenic activity. Therefore, in addition to DNp73 as a prognostic indicator, these data
suggest that DNp73 and Itch are potential targets for cancer therapy.
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