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Cyclin D type does not influence cell cycle response to DNA damage caused by ionizing radiation in multiple myeloma tumours
Author(s) -
Smith Dean,
Mann David,
Yong Kwee
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13982
Subject(s) - cyclin d1 , cell cycle , cyclin d2 , retinoblastoma protein , cell cycle checkpoint , dna damage , cyclin a , cyclin b , cancer research , cyclin d , biology , cyclin e , microbiology and biotechnology , cyclin b1 , cyclin , chemistry , cyclin dependent kinase 1 , apoptosis , dna , genetics
Summary Multiple myeloma ( MM ) is characterized by over‐expression of cyclin D1 ( CCND 1) or D2 ( CCND 2), which control G1 phase cell‐cycle progression. Proteolytic degradation of CCND 1 (but not CCND 2), resulting in G1 arrest, is reported in non‐ MM cells post‐ DNA damage, affecting DNA repair and survival. We examined the effect of ionizing radiation ( IR ) on D‐cyclin levels and cell‐cycle kinetics of MM cells, exploring differences based on D‐cyclin expression. We showed that CCND 1 is downregulated, whereas CCND 2 is not, following IR . This did not lead to hypo‐phosphorylation of retinoblastoma protein or G1 arrest. Both CCND 1‐ and CCND 2‐expressing MM cells arrested in S/G2/M, and did not differ in other cell‐cycle proteins or sensitivity to IR . When treated with a CDK 4/6 inhibitor, both CCND 1 and CCND 2 MM cells arrested in G1 and therefore are subject to physiological regulation at this checkpoint. Immunoprecipitation showed that, despite CCND 1 degradation following IR , sufficient protein remains bound to CDK 4/6 to prevent G1 arrest. Aberrant expression of CCND 1 driven from the IGH promoter in t(11;14) MM cells maintains progression through G1 to arrest in S/G2/M. Differential expression of D‐cyclin does not appear to affect cell‐cycle response to IR , and is unlikely to underlie differential sensitivity to DNA damage.