The success of cytotoxic anticancer agents is determined by the ability of the tumor cell to activate a genetically programmed process of autonomous cell death, termed apoptosis, in response to induced DNA damage. The majority of human cancers harbor genetic alterations that dictate a decreased susceptibility to apoptosis and consequent cross-resistance to multiple anticancer agents. The p53 tumor suppressor gene, a critical component for the induction of DNA damage induced apoptosis, is frequently inactivated in human cancers. The development of effective antineoplastic strategies against p53 deficient human cancers is contingent upon an elucidation of the fundamental molecular mechanisms of DNA damage induced apoptosis. The cellular response to DNA damage involves the transient arrest of cell cycle progression at the G2/M transition by inactivation of p34 cdc2 kinase, thereby allowing time for DNA repair. Failure to inhibit p34cdc2 in the presence of damaged or unreplicated DNA results in lethal mitotic phenotypes (termed """"""""mitotic catastrophes"""""""") that exhibit features reminiscent of apoptosis. Preliminary studies suggest that (I) DNA damage induced apoptosis requires activation of p34cdc2 kinase, and (ii) activation of p34cdc2 kinase during apoptosis is dependent upon a family of evolutionarily conserved cysteine proteases related to interleukin-1beta converting enzyme (ICE) and CPP32beta(Yama/Apopain). These observations suggest that the activity of ICE/CPP32Beta-related proteases and p32cdc2 kinase. These studies are designed to provide a foundation for the development of experimental therapeutic strategies against p53- deficient cancers based upon modulating specific biochemical and cell cycle regulatory determinants of apoptosis.
| Ravi, R; Mookerjee, B; Bhujwalla, Z M et al. (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34-44 |
| Ravi, R; Mookerjee, B; van Hensbergen, Y et al. (1998) p53-mediated repression of nuclear factor-kappaB RelA via the transcriptional integrator p300. Cancer Res 58:4531-6 |
| Ravi, R; Bedi, A; Fuchs, E J et al. (1998) CD95 (Fas)-induced caspase-mediated proteolysis of NF-kappaB. Cancer Res 58:882-6 |
| Fuchs, E J; McKenna, K A; Bedi, A (1997) p53-dependent DNA damage-induced apoptosis requires Fas/APO-1-independent activation of CPP32beta. Cancer Res 57:2550-4 |
