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A Skp2 Autoinduction Loop and Restriction Point Control

Yuval Yung, Janice L. Walker, James M. Roberts and Richard K. Assoian
The Journal of Cell Biology
Vol. 178, No. 5 (Aug. 27, 2007), pp. 741-747
Stable URL: http://www.jstor.org/stable/30050524
Page Count: 7
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A Skp2 Autoinduction Loop and Restriction Point Control
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Abstract

We describe a self-amplifying feedback loop that autoinduces Skp2 during G1 phase progression. This loop, which contains Skp2 itself, $p27^{kip1}$ (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 ($p27^{T187A}$), 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.

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