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(Received for publication, May
10, 1995) From the The cyclin-dependent kinase (Cdk) inhibitor
p21
Volume 270,
Number 29,
Issue of July 21, pp. 17060-17063, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Is Involved in
Proliferating Cell Nuclear Antigen Binding but Does Not Appear to Be
Required for Growth Inhibition
has been
found to be involved in cell senescence, cell cycle arrest, and
differentiation. p21
inhibits the activity of
several Cdks, in contrast to other inhibitors such as p15
and p16
, which act on specific
cyclin-Cdk complexes. Of interest were reports that p21
also bound proliferating cell nuclear antigen (PCNA), an
auxiliary protein for DNA polymerase
, and inhibited DNA
replication but not DNA repair in vitro. To better understand
the function of this interaction in vivo, we first determined
the region of p21
that was needed for PCNA
binding. Analysis of deletion mutants of p21
,
which covered the majority of the protein, revealed that deletion of
either amino acids 142-147 or 149-154 resulted in loss of
ability to bind a glutathione S-transferase-PCNA fusion
protein. Site-directed mutagenesis in this region led to the
identification of the PCNA binding motif
RQXXMTXFYXXXR and demonstrated that
mutation of either amino acid Met-147 or Phe-150 resulted in almost
complete ablation of PCNA binding. Interestingly, when we determined
DNA synthesis inhibitory activity of deletion mutants or point mutants
that were unable to bind Cdk2 and/or PCNA, we found that loss of
binding to PCNA did not affect inhibitory activity, whereas lack of
Cdk2 binding greatly reduced the same. This result suggests that the
primary mechanism for inhibition of DNA synthesis by p21
occurs via inhibition of Cdk activity.
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