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Apoptosis induced by overexpression of hMSH2 or hMLH1
H Zhang1, B Richards, T Wilson
1Department of Oncological Sciences, Huntsman Cancer Institute at the University of Utah, Salt Lake City 84112, USA.
Abstract:
Mutations of the mismatch repair genes hMSH2 and hMLH1 have been found in a high proportion of individuals with hereditary nonpolyposis colon cancer (HNPCC), establishing the link between mismatch repair and cancer. Tumor cell lines that are deficient in mismatch repair develop a mutator phenotype that appears to drive the accumulation of mutations required for tumor development. However, mutations of other mismatch repair genes such as hPMS2 can lead to a mutator phenotype, although inherited mutations of these genes are rare in HNPCC families. Here, we show that overexpression of hMSH2 or hMLH1 but not of hMSH3, hMSH6, or hPMS2 induces apoptosis in either repair-proficient or -deficient cells. Furthermore, primary mouse embryo fibroblasts derived from Msh2-deficient mice lose their ability to undergo apoptosis after treatment with N-methyl-N'-nitro-N-nitrosoguanidine. These results suggest that the mismatch repair proteins hMSH2 and hMLH1 may be components of a pathway that influences apoptosis. We consider the possibility that loss of apoptosis as a result of hMSH2 or hMLH1 deficiency may be an additional factor in cancer predisposition in HNPCC.
Insights
Mismatch repair genes hMSH2 and hMLH1 are crucial for preventing cancer. Their deficiency may lead to hereditary nonpolyposis colon cancer (HNPCC) by disrupting apoptosis, a key cell death pathway.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Mutations in mismatch repair (MMR) genes hMSH2 and hMLH1 are strongly linked to hereditary nonpolyposis colon cancer (HNPCC).
- MMR-deficient tumors exhibit a mutator phenotype, accumulating mutations that drive tumor development.
- While other MMR genes like hPMS2 can cause a mutator phenotype, inherited mutations are rare in HNPCC.
Purpose of the Study:
- To investigate the role of specific MMR proteins (hMSH2, hMLH1, hMSH3, hMSH6, hPMS2) in apoptosis.
- To determine if Msh2 deficiency impacts apoptosis induction in mouse cells.
Main Methods:
- Overexpression of MMR genes in repair-proficient and -deficient cell lines.
- Treatment of primary mouse embryo fibroblasts (MEFs) from Msh2-deficient mice with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).
- Assessment of apoptosis induction in response to gene manipulation and chemical treatment.
Main Results:
- Overexpression of hMSH2 or hMLH1 induced apoptosis in both repair-proficient and -deficient cells.
- hMSH3, hMSH6, and hPMS2 overexpression did not trigger apoptosis.
- Msh2-deficient MEFs showed a reduced ability to undergo apoptosis after MNNG treatment.
Conclusions:
- The MMR proteins hMSH2 and hMLH1 appear to be integral components of a pathway regulating apoptosis.
- Loss of hMSH2 or hMLH1 function may contribute to cancer predisposition in HNPCC by impairing apoptosis.
- This suggests an additional mechanism beyond the mutator phenotype linking MMR deficiency to cancer.