Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis.

Abstract:

:Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene-transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2-deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the cell cycle, we explored a hypothesized role for Cdk2 dysregulation in this effect through conditional deletions of both genes. In oncogene-transformed MEFs lacking both genes, tumor formation was strongly suppressed in a manner associated with decreased proliferation, premature senescence, and error-prone recovery from serum deprivation after immortalization. Whereas loss of cyclin A2 led to a compensatory increase in Cdk1 activity, this did not occur with loss of both Cdk2 and cyclin A2. Our work offers a rationale to explore combinations of Cdk1 and Cdk2 inhibitors as a general approach in cancer therapy.

journal_name

Cancer Res

journal_title

Cancer research

authors

Gopinathan L,Tan SL,Padmakumar VC,Coppola V,Tessarollo L,Kaldis P

doi

10.1158/0008-5472.CAN-13-3440

subject

Has Abstract

pub_date

2014-07-15 00:00:00

pages

3870-9

issue

14

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-13-3440

journal_volume

74

pub_type

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