Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage.
Khosravi, R, et al.
Proc. Natl. Acad. Sci. U.S.A., 96: 14973-7 (1999)
1999
Show Abstract
The p53 tumor-suppressor protein, a key regulator of cellular responses to genotoxic stress, is stabilized and activated after DNA damage. This process is associated with posttranslational modifications of p53, some of which are mediated by the ATM protein kinase. However, these modifications alone may not account in full for p53 stabilization. p53's stability and activity are negatively regulated by the oncoprotein MDM2, whose gene is activated by p53. Conceivably, p53 function may be modulated by modifications of MDM2 as well. We show here that after treatment of cells with ionizing radiation or a radiomimetic chemical, but not UV radiation, MDM2 is phosphorylated rapidly in an ATM-dependent manner. This phosphorylation is independent of p53 and the DNA-dependent protein kinase. Furthermore, MDM2 is directly phosphorylated by ATM in vitro. These findings suggest that in response to DNA strand breaks, ATM may promote p53 activity and stability by mediating simultaneous phosphorylation of both partners of the p53-MDM2 autoregulatory feedback loop. | 10611322
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Identification of the MDM2 oncoprotein as a substrate for CPP32-like apoptotic proteases.
Erhardt, P, et al.
J. Biol. Chem., 272: 15049-52 (1997)
1997
Show Abstract
Programmed cell death is mediated by members of the interleukin 1-beta convertase family of proteases, which are activated in response to diverse cell death stimuli. However, the key substrates of these proteases that are responsible for apoptotic cell death have not been identified. Here we report that the MDM2 oncoprotein is cleaved by members of the CPP32 subfamily of interleukin 1-beta convertase proteases both in vitro and in vivo, resulting in the disappearance of MDM2 from apoptotic cells. Because MDM2 functions as a negative regulator of the p53 tumor suppressor and because p53 induces apoptosis in response to a variety of stimuli, this cleavage of MDM2 by CPP32-like proteases may result in deregulation of p53 and contribute directly to the process of apoptotic cell death. | 9182520
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