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Published online
doi:10.1083/jcb.200703034
The Journal of Cell Biology, Vol. 178, No. 5, 741-747
The Rockefeller University Press, 0021-9525 $30.00
© Yung et al.
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A Skp2 autoinduction loop and restriction point control



Yuval Yung1, Janice L. Walker1, James M. Roberts2, and Richard K. Assoian1

1 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
2 Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Correspondence to Richard K. Assoian: rka{at}pharm.med.upenn.edu

We describe a self-amplifying feedback loop that autoinduces Skp2 during G1 phase progression. This loop, which contains Skp2 itself, p27kip1 (p27), cyclin E–cyclin dependent kinase 2, and the retinoblastoma protein, is closed through a newly identified, conserved E2F site in the Skp2 promoter. Interference with the loop, by knockin of a Skp2-resistant p27 mutant (p27T187A), delays passage through the restriction point but does not interfere with S phase entry under continuous serum stimulation. Skp2 knock down inhibits S phase entry in nontransformed mouse embryonic fibroblasts but not in human papilloma virus–E7 expressing fibroblasts. We propose that the essential role for Skp2-dependent degradation of p27 is in the formation of an autoinduction loop that selectively controls the transition to mitogen-independence, and that Skp2-dependent proteolysis may be dispensable when pocket proteins are constitutively inactivated.

Abbreviations used in this paper: Ad-hSkp2, adenovirus encoding human Skp2; APC/Ccdh1, anaphase-promoting complex/cyclosome and its activator Cdh1; ChIP, chromatin immunoprecipitation; E7, human papilloma virus–E7; MEF, mouse embryo fibroblast; p27, p27kip1; QPCR, quantitative real-time RT-PCR; Rb, retinoblastoma protein.


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