The role of oncogenic Ras in human skin tumorigenesis depends on the clonogenic potential of the founding keratinocytes

Journal of Cell Science
Riccardo MaurelliElena Dellambra

Abstract

The role of Ras in human skin tumorigenesis induction is still ambiguous. Overexpression of oncogenic Ras causes premature senescence in cultured human cells and hyperplasia in transgenic mice. Here, we investigated whether the oncogenic insult outcome might depend on the nature of the founding keratinocyte. We demonstrate that overexpression of the constitutively active Ras-V12 induces senescence in primary human keratinocyte cultures, but that some cells escape senescence and proliferate indefinitely. Ras overexpression in transient-amplifying- or stem-cell-enriched cultures shows that p16 (encoded by CDKN2A) levels are crucial for the final result. Indeed, transient-amplifying keratinocytes expressing high levels of p16 are sensitive to Ras-V12-induced senescence, whereas cells with high proliferative potential, but that do not display p16, are resistant. The subpopulation that sustains the indefinite culture growth exhibits stem cell features. Bypass of senescence correlates with inhibition of the pRb (also known as RB1) pathway and resumption of telomerase reverse transcriptase (TERT) activity. Immortalization is also sustained by activation of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) and Akt pathways. Mor...Continue Reading

References

Apr 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·Y Barrandon, H Green
Nov 26, 1996·Proceedings of the National Academy of Sciences of the United States of America·A S JonasonD E Brash
Aug 18, 1999·Proceedings of the National Academy of Sciences of the United States of America·R M AlaniK Münger
Jul 26, 2000·The Journal of Biological Chemistry·B J NickoloffM O Diaz
Mar 15, 2001·Proceedings of the National Academy of Sciences of the United States of America·G PellegriniM De Luca
Jun 28, 2001·Proceedings of the National Academy of Sciences of the United States of America·R M AlaniC B Shifflett
Oct 3, 2002·Nature Medicine·Mirella LazarovPaul A Khavari
Aug 13, 2003·The EMBO Journal·Christian M BeauséjourJudith Campisi
Mar 17, 2004·Molecular and Cellular Biology·Jennifer A Benanti, Denise A Galloway
Jun 7, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Riccardo MaurelliElena Dellambra
Oct 12, 2007·Physiology·Rebecca Leadem Daugherty, Cara J Gottardi
Nov 13, 2009·The Journal of Investigative Dermatology·Sonia CordiscoElena Dellambra
Nov 18, 2010·British Journal of Cancer·F KernM Baccarini
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Apr 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Gaëlle LapougeCédric Blanpain
Apr 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Andrew C WhiteWilliam E Lowry
Oct 21, 2011·The Journal of Investigative Dermatology·Girish K PatelJonathan C Vogel
May 15, 2012·Cancer Letters·Khanh ThieuDavid M Owens
Sep 6, 2012·Proceedings of the National Academy of Sciences of the United States of America·Paola TucciGerry Melino
Oct 6, 2012·Seminars in Cell & Developmental Biology·Yann BarrandonAriane Rochat

❮ Previous
Next ❯

Citations

Jul 15, 2017·Cellular and Molecular Life Sciences : CMLS·Corinne AbbadieAlbin Pourtier
Sep 16, 2020·The Journal of Investigative Dermatology·Lavinia TinaburriElena Dellambra

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Epigenetics and Senescence (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may be involved in regulating senescence in cancer cells. This feed captures the latest research on cancer epigenetics and senescence.