atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity

Abstract

Mutations in atm and p53 cause the human cancer-associated diseases ataxia-telangiectasia and Li-Fraumeni syndrome, respectively. The two genes are believed to interact in a number of pathways, including regulation of DNA damage-induced cell-cycle checkpoints, apoptosis and radiation sensitivity, and cellular proliferation. Atm-null mice, as well as those null for p53, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development. To study the interactions of these two genes on an organismal level, we bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations. Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumour formation relative to singly null mice, indicating that both genes collaborate in a significant manner to prevent tumorigenesis. With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance. This implies that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent. Finally-and in contrast to prior predictions-atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumours.

Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress

“…This suggests that di erences in the cellular background may interact with the Atm/p53 pathway to modulate activation of speci®c downstream p53 functions. Finally, mice doubly null for both atm and p53 show complete resistance to radiation-induced apoptosis along with more rapid formation of tumors than seen with the knock-out of either gene alone (Westphal et al, 1997). This observation supports the idea that p53 response is not the only e ector of the Atm-regulated radiation response, as the pathways do not completely overlap.…”

Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest

“…Now KILLER/DR5 can be added to the list of p53 target genes which are impaired when the ATM-p53 pathway is disrupted. Interestingly, recent studies involving ATM null mice have found a tissuespeci®c dependence of p53 on ATM and have suggested that a ATM independent regulation of p53 activation and its resulting transcriptional activation exists (Barlow et al, 1997;Westphal et al, 1997;Herzog et al, 1998). It is clear that the de®ciency in p53 stabilization in AT-de®cient cells is relative, not absolute.…”

The role of ATM in DNA damage responses and cancer

“…However, the majority of evidence indicates that in most cases, cells defective in ATM are either normal or de®cient in their ability to undergo apoptosis in response to IR, although AT cells have been observed to be more sensitive to undergoing spontaneous apoptosis in culture (Enns et al, 1998;Barlow et al, 1997;Herzog et al, 1998;Westphal et al, 1997;Duchaud et al, 1996;Elson et al, 1996). In fact, a signi®cant component of radiosensitization caused by loss of ATM function may be largely independent of p53 status suggesting that enhanced p53-dependent apoptosis is not the primary cause of radiosensitization in AT (Westphal et al, 1998).…”

“…Thus, it was not surprising to ®nd thymocytes from ATM7/7 mice to be at least partially resistant to apoptosis induced by IR due to the dependence of p53 function on ATM Westphal et al, 1997). Upon closer examination however, Barlow et al (1997) found that when analysed at early time points after exposure of ATM7/7 mice to IR, thymocyte p53-dependent apoptosis appeared to be perfectly normal, even though G1 cell cycle checkpoint function was abrogated.…”

“…The ability of p53 to suppress oncogenesis has been linked to its abilities to mediate G1 cell cycle arrest, promote genetic stability, and trigger apoptosis in response to DNA strand breaks caused by genotoxic agents and programmed gene rearrangements (Morgan and Kastan, 1997b;White, 1996;Canman and Kastan, 1997). Tumor formation is dramatically accelerated in mice lacking both p53 and ATM as compared to mice having deletions in either gene alone suggesting that one or both of these proteins possess additional, independent functions in suppressing tumorigenesis (Westphal et al, 1997). The challenge for the future will be to determine whether cancer susceptibility in AT is primarily due to the loss of a critical signaling pathway to p53 or to parallel pathways that govern the transition through other phases of the cell cycle or regulate chromosomal repair (Meyn, 1995;Hartwell and Kastan, 1994;Jeggo et al, 1998).…”