Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 18 August 2009
Vol. 2, Issue 84, p. ra44
[DOI: 10.1126/scisignal.2000053]

RESEARCH ARTICLES

Differential p53-Independent Outcomes of p19Arf Loss in Oncogenesis

Zhenbang Chen1,2*, Arkaitz Carracedo1,2, Hui-Kuan Lin2{dagger}, Jason A. Koutcher3, Nille Behrendt2, Ainara Egia1,2, Andrea Alimonti1,2, Brett S. Carver4, William Gerald2, Julie Teruya-Feldstein2, Massimo Loda5, and Pier Paolo Pandolfi1,2{ddagger}

1 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, New Research Building, 330 Brookline Avenue, Boston, MA 02115, USA.
2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA.
3 Departments of Medicine, Radiology and Medical Physics, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, NY 10021, USA.
4 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
5 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

* Present address: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Boulevard, Nashville, TN 37208–3599, USA.

{dagger} Present address: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

Abstract: One reported function of the tumor suppressor p19Arf is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19Arf, p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19Arf in prostate epithelium does not accelerate—but rather partially inhibits—the prostate cancer phenotype of Pten-deficient mice. Moreover, cellular senescence and a further decrease in the number of pre-neoplastic glands were observed in prostates of the Pten-p19Arf double-mutant mice. In both prostate epithelium and primary mouse embryo fibroblasts (MEFs), the increase in p53 protein abundance found upon loss of Pten was unaffected by the simultaneous loss of p19Arf. However, in contrast to that in the prostate epithelium, p19Arf deficiency in MEFs lacking Pten abolished cell senescence and promoted hyperproliferation and transformation despite the unabated increase in p53 abundance. Consistent with the effect of p19Arf loss in Pten-deficient mouse prostate, we found that in human prostate cancers, loss of PTEN was not associated with loss of p14ARF (the human equivalent of mouse p19Arf). Collectively, these data reveal differential consequences of p19Arf inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway.

{ddagger} To whom correspondence should be addressed. E-mail: ppandolf{at}bidmc.harvard.edu

Citation: Z. Chen, A. Carracedo, H.-K. Lin, J. A. Koutcher, N. Behrendt, A. Egia, A. Alimonti, B. S. Carver, W. Gerald, J. Teruya-Feldstein, M. Loda, P. P. Pandolfi, Differential p53-Independent Outcomes of p19Arf Loss in Oncogenesis. Sci. Signal. 2, ra44 (2009).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Antagonistic TSC22D1 variants control BRAFE600-induced senescence.
C. Homig-Holzel, R. van Doorn, C. Vogel, M. Germann, M. G. Cecchini, E. Verdegaal, and D. S. Peeper (2011)
EMBO J. 30, 1753-1765
   Abstract »    Full Text »    PDF »
Molecular genetics of prostate cancer: new prospects for old challenges.
M. M. Shen and C. Abate-Shen (2010)
Genes & Dev. 24, 1967-2000
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882