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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.
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.
Insights
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.