The Role of Cyclin D1 in the Chemoresistance of Mantle Cell Lymphoma
Abstract
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 CDK5RAP3(C53), 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 CCND1/C53 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2016
- Accession Number
- AD1033279
Entities
People
- Vu Ngo