Cdk2 and Cdk4 Activities Are Dispensable for Tumorigenesis Caused by the Loss of p53

doi:10.1128/MCB.00952-08

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Molecular and Cellular Biology, May 2009, p. 2582-2593, Vol. 29, No. 10
0270-7306/09/$08.00+0 doi:10.1128/MCB.00952-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cdk2 and Cdk4 Activities Are Dispensable for Tumorigenesis Caused by the Loss of p53

V. C. Padmakumar,¹ Eiman Aleem,¹^, Cyril Berthet,¹^, Mary Beth Hilton,¹ and Philipp Kaldis¹^,2^*

Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute—Frederick, Bldg. 560/22-56, 1050 Boyles Street, Frederick, Maryland 21702-1201,¹ Institute of Molecular and Cell Biology (IMCB), Cell Division and Cancer Laboratory (PRK), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore²

Received 15 June 2008/ Returned for modification 17 July 2008/ Accepted 11 March 2009

The loss of p53 induces spontaneous tumors in mice, and p53mutations are found in approximately 50% of human tumors. Thesetumors are generally caused by a number of events, includinggenomic instability, checkpoint defects, mitotic defects, deregulationof transcriptional targets, impaired apoptosis, and G₁ deregulationor a combination of these effects. In order to determine therole of proteins involved in G₁ control in tumorigenesis, wefocused on Cdk2 and Cdk4, two cyclin-dependent kinases thatin association with cyclin E and cyclin D promote the G₁/S phasetransition. We analyzed the consequence of loss of Cdk2 in p53-nullanimals by generating Cdk2^–^/^– p53^–^/^–mice. These mice are viable and developed spontaneous tumors,predominantly lymphoblastic lymphomas, similar to p53^–^/^–mice. In contrast, the genotypes Cdk4^–^/^– p53^–^/^–were mostly lethal, with few exceptions, and Cdk2^–^/^–Cdk4^–^/^–p53^–^/^– mice die during embryogenesisat embryonic day 13.5. To study the oncogenic potential, wegenerated mouse embryonic fibroblasts (MEFs) and found thatp53^–^/^–, Cdk2^–^/^– p53^–^/^–,Cdk4^–^/^– p53^–^/^–, and Cdk2^–^/^–Cdk4^–^/^– p53^–^/^– MEFs grew at similarrates without entering senescence. Ras-transformed MEFs of thesegenotypes were able to form colonies in vitro and induce tumorsin nude mice. Our results suggest that tumorigenicity mediatedby p53 loss does not require either Cdk2 or Cdk4, which necessitatesconsidering the use of broad-spectrum cell cycle inhibitorsas a means of effective anti-Cdk cancer therapy.

* Corresponding author. Mailing address: Institute of Molecular and Cell Biology (IMCB), Cell Division and Cancer Laboratory (PRK), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore. Phone: 65 65869854. Fax: 65 67791117. E-mail: kaldis{at}imcb.a-star.edu.sg

Published ahead of print on 23 March 2009.

Present address: University of Alexandria, Faculty of Science,Alexandria, Egypt.

Present address: Oncodesign, 20 rue Jean Mazen, BP27627, Dijoncedex 21076, France.