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Identification of the MDM2 oncoprotein as a substrate for CPP32-like apoptotic proteases
P Erhardt1, K J Tomaselli, G M Cooper
1Division of Molecular Genetics, Dana-Farber Cancer Institute and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
The Journal of Biological Chemistry
|June 13, 1997
Summary
Members of the interleukin 1-beta convertase protease family cleave the MDM2 oncoprotein during programmed cell death. This cleavage may deregulate the p53 tumor suppressor, contributing to apoptosis.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Programmed cell death, or apoptosis, is crucial for development and tissue homeostasis.
- Interleukin 1-beta convertase (ICE)-family proteases are key mediators of apoptosis.
- The specific substrates of these proteases driving apoptosis remain largely unidentified.
Purpose of the Study:
- To identify key substrates of ICE-family proteases involved in apoptotic cell death.
- To investigate the interaction between MDM2 oncoprotein and CPP32-like proteases in apoptosis.
Main Methods:
- In vitro protease assays to assess MDM2 cleavage by CPP32-like proteases.
- In vivo studies in apoptotic cells to observe MDM2 disappearance.
- Analysis of the regulatory relationship between MDM2, p53, and apoptosis.
Main Results:
- MDM2 oncoprotein is directly cleaved by CPP32 subfamily proteases.
- Cleavage of MDM2 by CPP32-like proteases leads to its disappearance from apoptotic cells.
- MDM2 negatively regulates the p53 tumor suppressor, which induces apoptosis.
Conclusions:
- Cleavage of MDM2 by CPP32-like proteases is a significant event in apoptosis.
- This cleavage may lead to the deregulation of p53 tumor suppressor function.
- The MDM2-p53 pathway is a critical target in understanding and potentially manipulating apoptotic cell death.