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Journal of Virology, October 2001, p. 9844-9856, Vol. 75, No. 20
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.20.9844-9856.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Inactivation of p21 by E1A Leads to the Induction
of Apoptosis in DNA-Damaged Cells
Debasis
Chattopadhyay,
Mrinal
K.
Ghosh,
Asoke
Mal, and
Marian L.
Harter*
Department of Molecular Biology, Lerner
Research Institute, The Cleveland Clinic Foundation, Cleveland,
Ohio 44195
Received 19 March 2001/Accepted 30 June 2001
A major impediment to successful chemotherapy is the propensity for
some tumor cells to undergo cell cycle arrest rather than apoptosis. It
is well established, however, that the adenovirus E1A protein can
sensitize these cells to the induction of apoptosis by anticancer
agents. To further understand how E1A enhances chemosensitivity, we
have made use of a human colon carcinoma cell line (HCT116) which
typically undergoes cell cycle arrest in response to chemotherapeutic drugs. As seen by the analysis of E1A mutants, we show here that E1A
can induce apoptosis in these cells by neutralizing the activities of
the cyclin-dependent kinase inhibitor p21. E1A's ability to interact
with p21 and thereby restore Cdk2 activity in DNA-damaged cells
correlates with the reversal of G1 arrest, which in turn leads to apoptosis. Analysis of E1A mutants failing to bind p300 (also
called CBP) or Rb shows that they are almost identical to wild-type E1A
in their ability to initially overcome a G1 arrest in cells
after DNA damage, while an E1A mutant failing to bind p21 is not.
However, over time, this mutant, which can still target Rb, is far more
efficient in accumulating cells with a DNA content greater than
4N but is similar to wild-type E1A and the other E1A mutants in releasing cells from a p53-mediated G2 block
following chemotherapeutic treatment. Thus, we suggest that although
E1A requires the binding of p21 to create an optimum environment for apoptosis to occur in DNA-damaged cells, E1A's involvement in other
pathways may be contributing to this process as well. A model is
proposed to explain the implications of these findings.
*
Corresponding author. Mailing address: Department of
Molecular Biology, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Phone: (216) 444-0632. Fax: (216) 444-0512. E-mail: hartern{at}ccf.org.
Journal of Virology, October 2001, p. 9844-9856, Vol. 75, No. 20
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.20.9844-9856.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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