Butz, Nicole, Ruetz, Stephan, Natt, Francois, Hall, Jonathan, Weiler, Jan, Mestan, Juergen, Ducarre, Monique, Grossenbacher, Rita, Hauser, Patrick, Kempf, Dominique and Hofmann, Francesco (2005) The human ubiquitin-conjugating enzyme Cdc34 controls cellular proliferation through regulation of p27Kip1 protein levels. Experimental Cell Research, 303 (2). pp. 482-493. ISSN 0014-4827

Abstract

Ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27Kip1 was shown to be required for the activation of key cyclin-dependent kinases, thereby triggering the onset of DNA replication and cell cycle progression. Although the SCFSkp2 ubiquitin ligase has been reported to mediate p27Kip1 degradation, the nature of the human ubiquitin-conjugating enzyme involved in this process has not yet been determined at the cellular level. Here, we show that antisense oligonucleotides targeting the human ubiquitin-conjugating enzyme Cdc34 downregulate its expression, inhibit the degradation of p27Kip1, and prevent cellular proliferation. Elevation of p27Kip1 protein level is found to be the sole requirement for the inhibition of cellular proliferation induced upon downregulation of Cdc34. Indeed, reducing the expression of p27Kip1 with a specific antisense oligonucleotide is sufficient to reverse the anti-proliferative phenotype elicited by the Cdc34 antisense. Furthermore, downregulation of Cdc34 is found to specifically increase the abundance of the SCFSkp2) ubiquitin ligase substrate p27Kip1, but has no concomitant effect on the level of IkBalpha and beta-catenin, which are known substrates of a closely related SCF ligase.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... doi:10.1016/j.yexcr.2004.10.008
Additional Information:	author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords:	p27Kip1; Cdc34; Cell cycle; Ubiquitin; Ubiquitin-conjugating enzyme; IkBα; β-Catenin; Antisense; Laser scanning cytometry
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... doi:10.1016/j.yexcr.2004.10.008
Date Deposited:	14 Dec 2009 13:55
Last Modified:	31 Jan 2013 01:09
URI:	https://oak.novartis.com/id/eprint/696