Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation

Proceedings of the National Academy of Sciences of the United States of America
A W Lin, S W Lowe

Abstract

Chemically induced skin carcinomas in mice are a paradigm for epithelial neoplasia, where oncogenic ras mutations precede p53 and INK4a/ARF mutations during the progression toward malignancy. To explore the biological basis for these genetic interactions, we studied cellular responses to oncogenic ras in primary murine keratinocytes. In wild-type keratinocytes, ras induced a cell-cycle arrest that displayed some features of terminal differentiation and was accompanied by increased expression of the p19(ARF), p16(INK4a), and p53 tumor suppressors. In ARF-null keratinocytes, ras was unable to promote cell-cycle arrest, induce differentiation markers, or properly activate p53. Although oncogenic ras produced a substantial increase in both nucleolar and nucleoplasmic p19(ARF), Mdm2 did not relocalize to the nucleolus or to nuclear bodies but remained distributed throughout the nucleoplasm. This result suggests that p19(ARF) can activate p53 without overtly affecting Mdm2 subcellular localization. Nevertheless, like p53-null keratinocytes, ARF-null keratinocytes were transformed by oncogenic ras and rapidly formed carcinomas in vivo. Thus, oncogenic ras can activate the ARF-p53 program to suppress epithelial cell transformation. Dis...Continue Reading

References

Jan 1, 1988·Annals of the New York Academy of Sciences·S H YuspaD R Roop
Jul 1, 1983·The Journal of Investigative Dermatology·B A DaleS H Yuspa
Jan 1, 1994·Current Biology : CB·T JacksR A Weinberg
Feb 1, 1997·Current Opinion in Genetics & Development·M E Katz, F McCormick
Jul 8, 1998·Proceedings of the National Academy of Sciences of the United States of America·T KamijoC J Sherr
Aug 8, 1998·Genes & Development·E de StanchinaS W Lowe
Aug 28, 1998·Science·G Evan, T Littlewood
Sep 23, 1998·Nature·I PalmeroM Serrano
Oct 9, 1998·Genes & Development·C J Sherr
Jun 9, 1999·Proceedings of the National Academy of Sciences of the United States of America·W Tao, A J Levine
Aug 10, 1999·Nature·W C HahnR A Weinberg
Nov 13, 1999·Nature Cell Biology·J D WeberD Bar-Sagi
Jan 27, 2000·Cell·D Hanahan, R A Weinberg
Feb 19, 2000·Current Opinion in Genetics & Development·C J Sherr, J D Weber
Feb 26, 2000·Carcinogenesis·A Balmain, C C Harris
Mar 9, 2000·Nature Cell Biology·M A LohrumK H Vousden
Mar 25, 2000·Molecular and Cellular Biology·M MalumbresA Pellicer
Sep 20, 2000·Genes & Development·J D WeberG P Zambetti

❮ Previous
Next ❯

Citations

Jul 14, 2007·Cellular and Molecular Life Sciences : CMLS·J OmerovicI A Prior
Nov 11, 2003·Cellular Signalling·Robert A Mitchell
Oct 25, 2001·Cancer Letters·O Pluquet, P Hainaut
Sep 21, 2002·Biochimica Et Biophysica Acta·Nghia T V Le, Des R Richardson
Nov 8, 2001·Current Opinion in Cell Biology·M Serrano, M A Blasco
Mar 22, 2003·Current Opinion in Cell Biology·Christopher L Brooks, Wei Gu
Jan 16, 2002·Current Opinion in Genetics & Development·Sarah Drayton, Gordon Peters
Feb 8, 2003·Current Opinion in Genetics & Development·Scott W Lowe, Charles J Sherr
Feb 8, 2003·Current Opinion in Genetics & Development·Soyoung Lee, Clemens A Schmitt
Dec 4, 2004·Nature·Chaowei WuKonstantin Galaktionov
Apr 24, 2007·Nature Cell Biology·Christopher J SarkisianLewis A Chodosh
Sep 8, 2005·Nature Medicine·Masashi Narita, Scott W Lowe
Aug 22, 2006·Nature Reviews. Molecular Cell Biology·Jesús Gil, Gordon Peters
Jan 27, 2010·Oncogene·W C Gustafson, W A Weiss
Oct 6, 2005·Oncogene·J L RussellD G Johnson
Sep 10, 2010·The Journal of Biological Chemistry·Yanbin ZhengStephen X Skapek
Nov 28, 2008·Molecular Biology of the Cell·Zhixue LiuKeqiang Ye
Jun 18, 2002·The EMBO Journal·Sharon BrookesGordon Peters
Jan 16, 2002·Current Opinion in Oncology·Jill Bargonetti, James J Manfredi
Jan 11, 2007·Genes & Development·Frédérick A MalletteGerardo Ferbeyre
Jul 3, 2010·Genes & Development·Zhen ZhaoScott W Lowe
Aug 19, 2005·Genes & Development·William M KeyesAlea A Mills
Dec 12, 2001·Molecular and Cellular Biology·Chandrashekhar KorgaonkarDawn E Quelle
Apr 25, 2002·Molecular and Cellular Biology·Gerardo FerbeyreScott W Lowe
Feb 13, 2002·Molecular and Cellular Biology·Jamie L RussellDavid G Johnson
Jan 20, 2004·Molecular and Cellular Biology·Hayla K SlussStephen N Jones
Feb 3, 2005·Molecular and Cellular Biology·Chandrashekhar KorgaonkarDawn E Quelle
Feb 20, 2008·Biochemistry. Biokhimii︠a︡·P M Chumakov
Jul 10, 2012·The Journal of Clinical Investigation·Juan Guinea-ViniegraErwin F Wagner
Sep 11, 2013·The Journal of Clinical Investigation·Kwan-Hyuck BaekSandra Ryeom
Sep 19, 2008·PloS One·Lidia RuizAmancio Carnero
Mar 30, 2011·PloS One·Chiou-Mei LeeYu-Sun Chang
Feb 13, 2013·International Journal of Breast Cancer·Nandita Barnabas, Dalia Cohen
Jan 5, 2011·EMBO Molecular Medicine·Hyun Jung ParkPradip Raychaudhuri
Apr 15, 2015·Seminars in Cancer Biology·Paul YaswenXujuan Yang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Carcinoma, Squamous Cell

Basal cell carcinoma is a form of malignant skin cancer found on the head and neck regions and has low rates of metastasis. Discover the latest research on basal cell carcinoma here.

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.