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J. Biol. Chem., Vol. 276, Issue 48, 45433-45442, November 30, 2001
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From the Cancer Research Program, Garvan Institute of Medical
Research, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia
Estrogens regulate cell proliferation in target
tissues, including breast cancer by stimulating G1-S
phase transition. Activation of cyclin E·Cdk2 through abrogation of
the ability of p21WAF1/Cip1 to bind to and inhibit
cyclin-CDKs is a pivotal event in this process in MCF-7 breast cancer
cells. A proposed mechanism is p21 sequestration into cyclin
D1·Cdk4/6 complexes driven by estrogen-induced transcriptional
activation of cyclin D1 gene expression. However, we now
show that some E2-induced cyclin E·Cdk2 activation occurs in the absence of increased cyclin D1 levels and requires decreased p21
protein synthesis. Both mechanisms operate in the absence of major
changes in total p21 protein levels and instead target a low abundance
subset of newly synthesized p21. E2-induced activation of
cyclin E·Cdk2 is mimicked by targeted inhibition of nascent p21
expression by antisense p21 oligonucleotides. Cyclin E·Cdk2 activation is completely inhibited by a combination of antisense cyclin
D1 oligonucleotide transfection and elimination of the decrease in
nascent p21 by infection with adenoviral-p21. These findings strongly
support a central role for p21 in the early phase of
E2-induced mitogenesis and highlight a major functional role for newly synthesized CDK inhibitory proteins.
A Low Abundance Pool of Nascent p21WAF1/Cip1 Is
Targeted by Estrogen to Activate Cyclin E·Cdk2*
,
*
This work was supported in part by grants from the National
Health and Medical Research Council of Australia (NHMRC) and the New
South Wales Cancer Council.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.
Supported by an NHMRC Medical Postgraduate Research Scholarship
and a Leo & Jenny Cancer Foundation Cancer Research Grant.
§
Supported by an Australian Postgraduate Award.
¶
To whom correspondence should be addressed: Cancer Research
Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. Tel.:
61-2-9295-8322; Fax: 61-2-9295-8321; E-mail:
r.sutherland@garvan.org.au.
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