期刊
JOURNAL OF CELL BIOLOGY
卷 178, 期 5, 页码 741-747出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200703034
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- NCI NIH HHS [R25-CA101871, R25 CA101871] Funding Source: Medline
- NHLBI NIH HHS [R01 HL083367, HL083367] Funding Source: Medline
- NIGMS NIH HHS [F32 GM065031, F32-GM065031] Funding Source: Medline
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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