Grants and Contracts Details
Description
DNA mismatch repair (MMR) plays an important role in maintaining genomic stability as defects in MMR lead
to the development of cancer. In the past, the genome maintenance function of MMR had been attributed to
its ability to correct mismatches. However, increasing evidence suggests that the MMR system also
maintains genomic stability by promoting apoptosis in response to DNA damage induced by physical and
chemical agents, including environmental chemical carcinogens. This response is known to be dependent on
MutS and MutL homologs, and eliminates potentially carcinogenic cells from growing. The MMR-dependent
apoptosis appears to involve a signaling network, which transmits a DNA damage signal to the apoptotic
machinery to kill damaged cells. However, how the network works and what proteins are involved in this
network are poorly understood. This study aims to identify and characterize proteins that participate in
MMR-dependent apoptosis induced by environmental chemical carcinogens using a proteomic approach.
First, MMR-proficient and deficient cells will be treated with chemical carcinogens, and protein expression
profiles before and after treatments from these cells will be analyzed by 2-dimensional gel electrophoresis.
Proteins with differential expression will be subjected to mass spectromic analysis, and the resulting peptides
will be used for database homology searching to reveal their identities. Second, given the involvement of
protein phosphorylation or dephosphorylation in many signaling networks, we hypothesize that many proteins
participating in MMR-dependent apoptosis may be phosphorylated or dephosphorylated. To test this
hypothesis, proteins that are identified in this study and known previously to be involved in MMR-dependent
apoptosis will be analyzed for their phosphorylation status by 1-dimensional or 2-dimensional gels combined
with Western blot analysis, followed by mass spectrometry analysis. Data resulting from this project will
formulate the basis for more detailed investigations (R01 applications) to fully understand the molecular
'mechanism by which the MMR system maintains genomic stability by promoting apoptosis induced by
environmental chemical carcinogens. Because certain cancer chemotherapeutics, e.g., cisplatin and
'alkylating agents, can signal apoptosis in an MMR-dependent fashion, this study will also impact cancer
treatment, particularly cancers caused by MMR defects.
Status | Finished |
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Effective start/end date | 7/5/04 → 6/30/06 |
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