The human ubiquitin-conjugating enzyme Cdc34 controls cellular proliferation through regulation of p27{sup Kip1} protein levels

Journal Article · Tue Feb 15 04:00:00 EST 2005 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2004.10.008· OSTI ID:20717542

Butz, Nicole ^[1]; Ruetz, Stephan ^[1]; Natt, Francois ^[2]; Hall, Jonathan ^[2]; Weiler, Jan ^[2]; Mestan, Juergen ^[1]; Ducarre, Monique ^[1]; Grossenbacher, Rita ^[1]; Hauser, Patrick ^[1]; Kempf, Dominique ^[1]; Hofmann, Francesco ^[1]

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1. Novartis Institutes for BioMedical Research, Novartis Pharma AG, Disease Area Oncology, CH-4002 Basel (Switzerland)
2. Novartis Institutes for BioMedical Research, Novartis Pharma AG, Functional Genomics Area, 4002 Basel (Switzerland)

Ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27{sup Kip1} 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 SCF{sup Skp2} ubiquitin ligase has been reported to mediate p27{sup Kip1} 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 p27{sup Kip1}, and prevent cellular proliferation. Elevation of p27{sup Kip1} 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 p27{sup Kip1} 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 SCF{sup Skp2} ubiquitin ligase substrate p27{sup Kip1}, but has no concomitant effect on the level of IkB{alpha} and {beta}-catenin, which are known substrates of a closely related SCF ligase.

• OSTI ID: 20717542
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 303; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CELL CYCLE
CELL PROLIFERATION
DNA REPLICATION
GENE REGULATION
INHIBITION
LIGASES
OLIGONUCLEOTIDES
PHENOTYPE
PHOSPHOTRANSFERASES
SUBSTRATES