The Role of Cyclin D1 in the Chemoresistance of Mantle Cell Lymphoma
[Technical Report, Final Report]
City of Hope Beckman Research Institute
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Mantle cell lymphoma MCL is an aggressive B-cell malignancy characterized by over-expression of the cell cycle regulatory protein cyclin D1 CCND1. Increased CCND1 expression levels are strongly associated with shorter patient survival related toc hemoresistance, but little is known about the contribution of CCND1 to the resistant nature of MCL. On the basis of our preliminary data, we hypothesize that cyclin D1 plays a genome protective role through regulating expression of CDK5RAP3C53, which encodes a putative tumor suppressor known to antagonize the DNA checkpoint kinase CHEK1. We test this hypothesis by accomplishing the following two goals 1 To determine whether CCND1 protects the genome integrity of MCL through its downstream target C53 and 2 to determine the mechanism by which CCND1 regulates C53 expression. We found that C53 is required for inducing DNA damage following CCND1 depletion. In addition, CCND1 was found to physically interact with HDAC1 and increase HDAC1 recruitment to the C53 promoter.
- Medicine and Medical Research