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J. Biol. Chem., Vol. 277, Issue 30, 26741-26752, July 26, 2002
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From the Danish Cancer Society, Institute of Cancer Biology,
Strandboulevarden 49, Copenhagen DK-2100, Denmark
The "pocket proteins" pRb (retinoblastoma
tumor suppressor protein), p107, and p130 regulate cell proliferation
via phosphorylation-sensitive interactions with E2F transcription
factors and other proteins. We previously identified 22 in
vivo phosphorylation sites in human p130, including three sites
selectively targeted by cyclin D-Cdk4(6) kinases. Here we
assessed the effects of alanine substitution at the individual or
combined Cdk4(6)-specific sites in p130, compared with homologous sites
in p107 (Thr369/Ser650/Ser964). In
U-2-OS cells, the triple p107
Distinct Phosphorylation Events Regulate p130- and p107-mediated
Repression of E2F-4*
,
Cdk4* mutant strongly
inhibited E2F-4 activity and imposed a G1 arrest resistant
to cyclin D1 coexpression. In contrast, the p130Cdk4
mutant still responded to cyclin D1, suggesting the existence of
additional phosphorylation sites critical for E2F-4 regulation. Extensive mutagenesis, sensitive E2F reporter assays, and cell cycle
analyses allowed the identification of six such residues (serines 413, 639, 662, 1044, 1080, and 1112) that, in addition to the Cdk4-specific
sites, are necessary and sufficient for the regulation of E2F-4 and the
cell cycle by p130. Surprisingly, 12 of the in vivo
phosphorylation sites seem dispensable for E2F regulation and probably
modulate other functions of p130. These results further elucidate the
complex regulation of p130 and provide a molecular mechanism to explain
the differential control of p107 and p130 by
cyclin-dependent kinases.
*
This work was supported by grants from the Danish Cancer
Society, the Danish Medical Research Council, and the European Union.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Institute of Cancer
Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Tel.: 45-35-25-73-34; Fax: 45-35-25-77-21; E-mail:
KHH@biobase.dk.
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