Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis.

Abstract:

:The p53 tumor suppressor protein and the Akt/PKB kinase play important roles in the transduction of pro-apoptotic and anti-apoptotic signals, respectively. We provide evidence that conflicting signals transduced by Akt and p53 are integrated via negative feedback between the two pathways. On the one hand, the combination of ionizing radiation and survival factor deprivation, which leads to rapid apoptosis of IL-3 dependent DA-1 cells, entails a caspase- and p53-dependent destruction of Akt. This destruction of Akt is not a secondary consequence of apoptosis, since it is not seen when the same cells are triggered to undergo apoptosis under different conditions. On the other hand upon serum stimulation, when Akt becomes active and enhances cell survival, phosphorylation occurs at an Akt consensus site (serine 166) within the Mdm2 protein, a key regulator of p53 function. Taken together, our findings suggest that depending on the balance of signals, p53-dependent downregulation of Akt may promote an irreversible commitment to apoptotic cell death, whereas effective recruitment of Akt by appropriate survival signals may lead to activation of Mdm2, inactivation of p53, and eventually inhibition of p53-dependent apoptosis.

journal_name

Oncogene

journal_title

Oncogene

authors

Gottlieb TM,Leal JF,Seger R,Taya Y,Oren M

doi

10.1038/sj.onc.1205181

subject

Has Abstract

pub_date

2002-02-14 00:00:00

pages

1299-303

issue

8

eissn

0950-9232

issn

1476-5594

journal_volume

21

pub_type

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