The Role of Cyclin D1 in the Chemoresistance of Mantle Cell Lymphoma
Technical Report,01 Sep 2015,31 Aug 2016
City Of Hope Beckman Research Institute Duarte United States
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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 tochemo resistance, 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 focusing on the following specific aims 1 determine the effect of C53 depletion or overexpression on CCND1knockdown phenotypes 2 determine the role of CCND1 in regulating C53 expression. This report describes results from specific aim 1. We have found that C53 depletion reduces DNA damage and restores ATR signaling in CCND1-depleted MCL cells, consistent with the rescue of CCND1C53 double-knockdown cells and suggesting a role for C53 in mediating cytotoxicity of CCND1 knockdown. However, overexpression of C53 isoforms in the MCL cell line UPN-1 did not recapitulateCCND1 KD phenotypes as anticipated. We have proposed alternative approaches to address these discordant results.