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Molecular and Cellular Biology, June 2005, p. 4565-4578, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4565-4578.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Decreased Growth of Vhl–/– Fibrosarcomas Is Associated with Elevated Levels of Cyclin Kinase Inhibitors p21 and p27

Fiona A. Mack,1,2 Jagruti H. Patel,2 Mangatt P. Biju,3 Volker H. Haase,2,3 and M. Celeste Simon1,2,4*

Abramson Family Cancer Research Institute,1 Cell Growth and Cancer Graduate Group,2 Department of Medicine,3 Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 191044

Received 28 September 2004/ Returned for modification 8 November 2004/ Accepted 25 February 2005

Inactivating mutations within the von Hippel-Lindau (VHL) tumor suppressor gene predispose patients to develop a variety of highly vascularized tumors. pVHL targets {alpha} subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF), a critical regulator of energy metabolism, angiogenesis, hematopoiesis, and oxygen (O2) delivery, for ubiquitin-mediated degradation in an O2-dependent manner. To investigate the role of Vhl in cellular proliferation and tumorigenesis, we utilized mouse embryonic fibroblasts (MEFs), a common tool for analyzing cell cycle regulation, and generated Vhl–/– MEF-derived fibrosarcomas. Surprisingly, growth of both Vhl–/– MEFs and fibrosarcomas was impaired, although tumor vascularity was increased. Decreased proliferation of Vhl–/– MEFs was correlated with an overexpression of cyclin kinase inhibitors (CKIs) p21 and p27. The transcription of p21 and p27 is inhibited by c-Myc; therefore, the induction of CKIs was attributed to the ability of HIF to antagonize c-Myc activity. Indeed, p21 mRNA levels were elevated under normoxia in Vhl–/– MEFs, while c-Myc transcriptional activity was markedly reduced. Gene silencing of HIF-1{alpha} by small interfering RNA reduced p21 and p27 protein and mRNA levels in Vhl–/– MEFs. The induction of p21 and p27, mediated by constitutive activation of the HIF pathway, provides a mechanism for the decreased proliferation rates of Vhl–/– MEFs and fibrosarcomas. These results demonstrate that a loss of pVHL can induce growth arrest in certain cells types, which suggests that additional genetic mutations are necessary for VHL-associated tumorigenesis.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, Rm. 438 BRBII/III, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-5561. Fax: (215) 746-5511. E-mail: celeste2{at}mail.med.upenn.edu.

Molecular and Cellular Biology, June 2005, p. 4565-4578, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4565-4578.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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