This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Miliani de Marval, P. L.
Right arrow Articles by Rodriguez-Puebla, M. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Miliani de Marval, P. L.
Right arrow Articles by Rodriguez-Puebla, M. L.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2004, p. 7538-7547, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7538-7547.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Lack of Cyclin-Dependent Kinase 4 Inhibits c-myc Tumorigenic Activities in Epithelial Tissues

Paula L. Miliani de Marval,1 Everardo Macias,1 Robert Rounbehler,2 Piotr Sicinski,3 Hiroaki Kiyokawa,4 David G. Johnson,2 Claudio J. Conti,2 and Marcelo L. Rodriguez-Puebla1*

Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina,1 Science Park-Research Division, M. D. Anderson Cancer Center, Smithville, Texas,2 Department of Pathology, Harvard Medical School, Boston, Massachusetts,3 Department of Molecular Genetics, College of Medicine, University of Illinois, Chicago, Illinois4

Received 2 March 2004/ Returned for modification 6 April 2004/ Accepted 3 June 2004

The proto-oncogene c-myc encodes a transcription factor that is implicated in the regulation of cellular proliferation, differentiation, and apoptosis and that has also been found to be deregulated in several forms of human and experimental tumors. We have shown that forced expression of c-myc in epithelial tissues of transgenic mice (K5-Myc) resulted in keratinocyte hyperproliferation and the development of spontaneous tumors in the skin and oral cavity. Although a number of genes involved in cancer development are regulated by c-myc, the actual mechanisms leading to Myc-induced neoplasia are not known. Among the genes regulated by Myc is the cyclin-dependent kinase 4 (CDK4) gene. Interestingly, previous studies from our laboratory showed that the overexpression of CDK4 led to keratinocyte hyperproliferation, although no spontaneous tumor development was observed. Thus, we tested the hypothesis that CDK4 may be one of the critical downstream genes involved in Myc carcinogenesis. Our results showed that CDK4 inhibition in K5-Myc transgenic mice resulted in the complete inhibition of tumor development, suggesting that CDK4 is a critical mediator of tumor formation induced by deregulated Myc. Furthermore, a lack of CDK4 expression resulted in marked decreases in epidermal thickness and keratinocyte proliferation compared to the results obtained for K5-Myc littermates. Biochemical analysis of the K5-Myc epidermis showed that CDK4 mediates the proliferative activities of Myc by sequestering p21Cip1 and p27Kip1 and thereby indirectly activating CDK2 kinase activity. These results show that CDK4 mediates the proliferative and oncogenic activities of Myc in vivo through a mechanism that involves the sequestration of specific CDK inhibitors.

* Corresponding author. Mailing address: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough St., Raleigh, NC 27606. Phone: (919) 515-7409. Fax: (919) 515-3044. E-mail: marcelo_rodriguez-puebla{at}ncsu.edu.

Molecular and Cellular Biology, September 2004, p. 7538-7547, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7538-7547.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Macias, E., Miliani de Marval, P. L., De Siervi, A., Conti, C. J., Senderowicz, A. M., Rodriguez-Puebla, M. L. (2008). CDK2 Activation in Mouse Epidermis Induces Keratinocyte Proliferation but Does Not Affect Skin Tumor Development. Am. J. Pathol. 173: 526-535 [Abstract] [Full Text]  
  • Macias, E., Kim, Y., Miliani de Marval, P. L., Klein-Szanto, A., Rodriguez-Puebla, M. L. (2007). Cdk2 Deficiency Decreases ras/CDK4-Dependent Malignant Progression, but Not myc-Induced Tumorigenesis. Cancer Res. 67: 9713-9720 [Abstract] [Full Text]  
  • Cowling, V. H., D'Cruz, C. M., Chodosh, L. A., Cole, M. D. (2007). c-Myc Transforms Human Mammary Epithelial Cells through Repression of the Wnt Inhibitors DKK1 and SFRP1. Mol. Cell. Biol. 27: 5135-5146 [Abstract] [Full Text]  
  • Ramsey, M. R., Krishnamurthy, J., Pei, X.-H., Torrice, C., Lin, W., Carrasco, D. R., Ligon, K. L., Xiong, Y., Sharpless, N. E. (2007). Expression of p16Ink4a Compensates for p18Ink4c Loss in Cyclin-Dependent Kinase 4/6-Dependent Tumors and Tissues. Cancer Res. 67: 4732-4741 [Abstract] [Full Text]  
  • Flores, I., Evan, G., Blasco, M. A. (2006). Genetic analysis of myc and telomerase interactions in vivo.. Mol. Cell. Biol. 26: 6130-6138 [Abstract] [Full Text]  
  • Oskarsson, T., Essers, M. A. G., Dubois, N., Offner, S., Dubey, C., Roger, C., Metzger, D., Chambon, P., Hummler, E., Beard, P., Trumpp, A. (2006). Skin epidermis lacking the c-myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene. Genes Dev. 20: 2024-2029 [Abstract] [Full Text]  
  • Bockstaele, L., Kooken, H., Libert, F., Paternot, S., Dumont, J. E., de Launoit, Y., Roger, P. P., Coulonval, K. (2006). Regulated Activating Thr172 Phosphorylation of Cyclin-Dependent Kinase 4(CDK4): Its Relationship with Cyclins and CDK "Inhibitors".. Mol. Cell. Biol. 26: 5070-5085 [Abstract] [Full Text]  
  • Sherr, C. J., Roberts, J. M. (2004). Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 18: 2699-2711 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»