Overexpression of Cdk6-cyclin D3 highly sensitizes cells to physical and chemical transformation.
Virtually all mammalian cells express two seemingly redundant cyclin-D-dependent kinases (Cdk4 and Cdk6) and three partner cyclins (D1, D2 and D3) essential for the G(1)-S transition, with predominant expression of Cdk4 and D1 in mesenchymal cells and Cdk6 and D3 in hematopoietic cells. We recently found two novel functions for Cdk6 executed in fibroblasts although unlike Cdk4 it is dispensable for their proliferation. In the rat fibroblast NRK-49F cells, oncogenic stimulation recruits Cdk6 to participate in a step of the cell cycle start that seems to be critical for anchorage-independent S-phase onset. Among the kinase-D-type cyclin combinations, the Cdk6-cyclin-D3 complex has a unique ability to evade inhibition by cyclin-dependent kinase inhibitors and thereby control the cell's proliferative competence under growth-suppressive conditions. We describe here that 2-5-fold overexpression of both Cdk6 and D3 enhances by 5x10(3)-10(6)-fold the susceptibility of the BALB/c3T3 and C3H10T1/2 mouse fibroblast lines to ultraviolet irradiation- as well as 3-methylcholanthrene-induced transformation. This result suggests that deregulated expression of Cdk6 and cyclinD3 may predispose cells to malignant transformation, supporting the recent finding that cyclin D3 activated by chromosomal rearrangement is the causative gene of non-Hodgkin B lymphoma, in which Cdk6 is the major partner kinase.
Chen
Qiuhong
Q
Department of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Lin
Jie
J
Jinno
Shigeki
S
Okayama
Hiroto
H
D019943:Amino Acid Substitution; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D003062:Codon / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000502:physiology; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D015870:Gene Expression; D019940:Genes, bcl-1; D006801:Humans; D008748:Methylcholanthrene / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011836:Radiation Tolerance / Q000235:genetics; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014466:Ultraviolet Rays / Q000009:adverse effects
C534696:CCND3 protein, human; D002273:Carcinogens; C534697:Ccnd3 protein, mouse; C534698:Ccnd3 protein, rat; D003062:Codon; D056743:Cyclin D3; D016213:Cyclins; D018076:DNA, Complementary; D011993:Recombinant Fusion Proteins; D019938:Cyclin D1; D008748:Methylcholanthrene; C495911:CDK6 protein, human; C495912:Cdk6 protein, mouse; C495913:Cdk6 protein, rat; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases