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Inverse Regulation of Cyclin B1 by c-Myc and p53 and Induction of Tetraploidy by Cyclin B1 Overexpression¹

Section of Hematology/Oncology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania [X-Y. Y., L. G., E. V. P.]; Section of Hematology/Oncology, Department of Pediatrics, The University of Michigan School of Medicine, Ann Arbor, Michigan [N. D., M. W. L.]; Department of Biology, The University of North Carolina, Greensboro, Greensboro, North Carolina [K. K.]; The University of Michigan Cancer Center [M. W. L.] and The Cellular and Molecular Biology Program [M. W. L., E. V. P.], The University of Michigan Medical Center, Ann Arbor, Michigan; The Department of Molecular Genetics and Biochemistry, The University of Pittsburgh Medical Center [M. W. L., E. V. P.] and The University of Pittsburgh Cancer Institute [E. V. P.], Pittsburgh, Pennsylvania 15213

We have shown previously that mitotic spindle inhibitors allow the c-Myconcoprotein to uncouple mitosis from DNA synthesis, resulting in the acquisition of tetraploidy. This can also occur in the absence of spindle inhibition if c-Myc deregulation is combined with inactivation of the p53 tumor suppressor. Under these conditions, cyclin B1 protein is induced but retains its normal cell cycle regulation. We now show that the cyclin B1 promoter is directly but oppositely regulated by c-Myc and p53. Enforced expression of cyclin B1 also induces tetraploidy, either after mitotic spindle inhibition or in the absence of such inhibition if cyclin B1 is coexpressed with c-Myc. Cyclin B1 represents a new class of c-Myc target genes that is also regulated by p53. It is also the first identified downstream effector of c-Myc able to produce the chromosomal instability that characterizes virtually all tumor cells.

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