title: 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.
authors.affiliation: Authors' Affiliations: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research);
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Gopinathan
authors.affiliation: Authors' Affiliations: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research);
authors.forename: Shawn Lu Wen
authors.initials: SL
authors.lastname: Tan
authors.affiliation: National Cancer Institute, Mouse Cancer Genetics Program, NCI-Frederick, Frederick, Maryland.
authors.forename: V C
authors.initials: VC
authors.lastname: Padmakumar
authors.affiliation: National Cancer Institute, Mouse Cancer Genetics Program, NCI-Frederick, Frederick, Maryland.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.affiliation: National Cancer Institute, Mouse Cancer Genetics Program, NCI-Frederick, Frederick, Maryland.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Authors' Affiliations: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research); Department of Biochemistry, National University of Singapore (NUS), Singapore, Republic of Singapore; and kaldis@imcb.a-star.edu.sg.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaldis
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D056751:Cyclin A2 / Q000235:genetics* / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D047368:Tumor Burden / Q000235:genetics
chemical_list: D056751:Cyclin A2; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2