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  current news   Press   selected story    
     
  23 July 2014  
  Loss of Cdk2 and Cyclin A2 Impairs Cell Proliferation and Tumorigenesis
 
 



Authors
Lakshmi Gopinathan1, Shawn Lu Wen Tan1, V. C. Padmakumar3, Vincenzo Coppola3, Lino Tessarollo3and Philipp Kaldis1.2

1   Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and      Research)
2   Department of Biochemistry, National University of Singapore (NUS), Singapore, Republic of Singapore
3   National Cancer Institute, Mouse Cancer Genetics Program, NCI-Frederick, Frederick, Maryland

Published in Cancer Research on 15 July 2014.

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.

Figure Legend: Delayed tumorigenesis and impaired proliferation in the absence of cyclin A2 and Cdk2. (A) Liver tumors were induced by hydrodynamic tail vein injection of Ras/shRNA p53 in wild type (cyclin A2WT) or liver-specific cyclin A2 knockout (cyclin A2Liv-/-) mice. Tumor formation (assessed over 8 months) is delayed in cyclin A2Liv-/- mice. (B) Cyclin A2Liv-/- livers display a decreased Ki67 proliferative index (left); Ki67 immunohistochemistry in livers at 3 months following tumor induction (right). (C, D) Cyclin A2flox and Cdk2nullcyclin A2flox ROSA26-Cre-ERT2 MEFs were oncogenically transformed with Ras/p53DN and treated with 4-OHT to induce cyclin A2 knockout. Transformed MEFs were assessed for colony formation (C) or injected subcutaneously into nude mice (D). Cdk2nullcyclin A2null MEFs are resistant to transformation and display decreased tumorigenic potential.

For more information on Philipp KALDIS’s laboratory, click here.