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Functional regulation of D‐type cyclins by insulin‐like growth factor‐I and serum in multiple myeloma cells
Author(s) -
Glassford Janet,
Rabin Neil,
Lam Eric W.F.,
Yong Kwee L.
Publication year - 2007
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/j.1365-2141.2007.06789.x
Subject(s) - cyclin dependent kinase 6 , cyclin d3 , cyclin , cyclin d2 , cyclin d1 , cyclin dependent kinase , biology , cyclin d , cancer research , cell cycle , cyclin a , retinoblastoma protein , cyclin e1 , cyclin b , cyclin a2 , cyclin e , microbiology and biotechnology , endocrinology , cell , genetics
Summary D‐type cyclin genes are universally dysregulated in multiple myeloma (MM), but the functional consequences are unclear as D‐type cyclin gene expression does not correlate with proliferation or disease progression. We examined the protein expression and regulation of D‐type cyclins and other cell cycle regulators in human myeloma cell lines and primary CD138 + plasma cells (PCs). Cyclin D1, cyclin D2, cyclin dependent kinase (CDK) 4, CDK6, p27 Kip1 p18 INK4C and retinoblastoma protein (pRb) were absent in normal PCs, heterogeneously expressed in primary MM cells and positively correlated with disease activity/progression. Cyclins D1 and D2 complexed with both CDK4 and CDK6, suggesting that both phosphorylate pRb in MM. Furthermore, cyclin D2 expressed via either t(14;16) or t(4;14) IgH translocations was functionally upregulated by fetal calf serum or insulin‐like growth factor‐I, leading to pRb phosphorylation and cell cycle entry/progression, and in some cases inversely correlated with p27 Kip1 . However, pRb phosphorylation and cell cycle progression mediated by cyclin D1 expressed via t(11;14) was less dependent on exogenous stimuli. These data suggest that the presence or absence of specific IgH translocations underlying aberrant D‐type cyclin expression may influence their response to mitogens in the bone marrow microenvironment. We showed for the first time that D‐type cyclins are functionally regulated in MM, differentially responsive to exogenous growth factors and upregulated with disease progression.