Journalartikel

Jahr der Veröffentlichung: 2009

Seiten: 1748-1757

Zeitschrift: Cancer Research

Bandnummer: 69

Heftnummer: 5

ISSN: 0008-5472

eISSN: 1538-7445

Open Access Status: Green

DOI Link: https://doi.org/10.1158/0008-5472.CAN-08-1377

Verlag: American Association for Cancer Research

Abstract: 

Promoter hypermethylation preventing expression of the RAS association domain family 1 isoform A (RASSF1A) gene product is among the most abundant epigenetic deregulations in human cancer. Restoration of RASSF1A inhibits tumor cell growth in vitro and in murine xenograft models. Rassf1a-deficient mice feature increased spontaneous and carcinogen-induced tumor formation. Mechanistically, RASSF1A affects several cellular functions, such as microtubule dynamics, migration, proliferation, and apoptosis; however, its tumor-suppressive mechanism is incompletely understood. To study the functional consequences of RASSF1A expression in human cancer cells, we made use of a doxycycline-inducible expression system and a RASSF1A-deficient lung cancer cell line. We observed that RASSF1A induces cell cycle arrest in G1 phase and senescence in vitro and in tumors established in immunodeficient mice. RASSF1A-mediated growth inhibition was accompanied by the up-regulation of the cyclin-dependent kinase inhibitor p21^Cip1/Waf1 and proceeded independently of p53, p14^Arf, and p16^Ink4a. Loss of p21^Cip1/Waf1 or coexpression of the human papilloma virus 16 oncoprotein E7 was found to override RASSF1A-induced cell cycle arrest and senescence. Conditional RASSF1A affected mitogen-activated protein kinase and protein kinase B/Akt signaling to up-regulate p21^Cip1/Waf1 and to facilitate its nuclear localization. In summary, RASSF1A can mediate cell cycle arrest and senescence in human cancer cells by p53-independent regulation of p21^Cip1/Waf1.

Harvard-Zitierstil: Thaler, S., Hähnel, P., Schad, A., Dammann, R. and Schuler, M. (2009) RASSF1A mediates p21Cip1/Waf1-dependent cell cycle arrest and senescence through modulation of the Raf-MEK-ERK pathway and inhibition of Akt, Cancer Research, 69(5), pp. 1748-1757. https://doi.org/10.1158/0008-5472.CAN-08-1377

APA-Zitierstil: Thaler, S., Hähnel, P., Schad, A., Dammann, R., & Schuler, M. (2009). RASSF1A mediates p21Cip1/Waf1-dependent cell cycle arrest and senescence through modulation of the Raf-MEK-ERK pathway and inhibition of Akt. Cancer Research. 69(5), 1748-1757. https://doi.org/10.1158/0008-5472.CAN-08-1377