A Critical Role for Cyclin C in Promotion of the Hematopoietic Cell Cycle by Cooperation with c-Myc

ABSTRACT

Cyclin C, a putative G₁ cyclin, was originally isolated through its ability to complement a Saccharomyces cerevisiae strain lacking the G₁ cyclin geneCLN1-3. Unlike cyclins D1 and E, the other two G₁ cyclins obtained by the same approach and subsequently shown to play important roles during the G₁/S transition, there is thus far no evidence to support the hypothesis that cyclin C is indeed critical for the promotion of cell cycle progression. In BAF-B03 cells, an interleukin 3 (IL-3)-dependent murine pro-B-cell line, cyclin C gene mRNA was induced at the G₁/S phase upon IL-3 stimulation and reached a maximal level in the S phase. Enforced expression of exogenous cyclin C in this cell line failed to alter its growth properties. In the present study, we examined whether cyclin C is capable of cooperating with the cytokine-responsive immediate-early gene products c-Myc and c-Fos in the promotion of cell proliferation. We found that cyclin C is able to cooperate functionally with c-Myc, but not c-Fos, to induce both BAF-B03 cell proliferation in a cytokine-independent fashion and the formation of cell clusters. Furthermore, cyclin C was primarily responsible for the induction of cdc2 gene expression. Our data define a novel role for cyclin C in the regulation of both the G₁/S and G₂/M phases of the cell cycle, and this effect appears to be independent of the activity of CDK8 in the control of transcription.

ACKNOWLEDGMENTS

We are grateful to R. A. Weinberg for human cyclin C, E, D1, and D3 expression plasmids (Rc-cycC, Rc-cycE, Rc-cycD1 and Rc-cycD3, respectively); Y. Nakabeppu for human c-fos plasmid; E. A. Nigg for pCMV-myc-tagged human cdk8 and pCMV-myc-tagged cdk8^AMG mutant plasmids; B. Rudolph for MycER and mock retroviral packaging GP+E-86 cells; E. Lee for anti-human cyclin C and anti-CDK8 antibodies; and T. L. Born for cyclin A and cdc2 promoter-luciferase reporter genes. We also thank A. Kukula for critical reading of the manuscript.

This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas provided by the Ministry of Education, Science, Sports and Culture, Japan; Nippon Boehringer Ingelheim Co., Ltd., Kawanishi Pharma Research Institute; the Kato Memorial Bioscience Foundation; and The Naito Foundation. Z.-J. L. was supported by a Grant-in-Aid for Japan Society for the Promotion of Science Fellows.