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Mutant p53 rescues human diploid cells from senescence without inhibiting the induction of SDI1/WAF1

Mutant p53 rescues human diploid cells from senescence without inhibiting the induction of SDI1/WAF1
Mutant p53 rescues human diploid cells from senescence without inhibiting the induction of SDI1/WAF1
Although the cyclin-dependent kinase inhibitor p21SDI1 (WAF1/CIP1) has been proposed as the mediator of p53-induced cell cycle arrest following DNA damage, several stimuli now appear to induce SDI1 independent of p53 function. We have examined the behavior of p53 and SDI1 in an isogeneic model by manipulating p53 status in normal diploid human fibroblasts using an amphotropic retroviral vector. Following DNA strand break damage induced by bleomycin, both SDI1 induction and G1-S cell cycle arrest are p53 dependent, consistent with SDI1 being the key mediator. In contrast, in cellular senescence (and following UV irradiation), induction of SDI1 occurs independent of p53 function yet growth arrest is still p53 dependent. We conclude (a) that redundant pathways exist for induction of SDI1, but that (b) SDI1, while perhaps necessary, is not sufficient for inhibition of cell cycle progression, requiring the cooperation of an additional factor (possibly another cyclin-dependent kinase inhibitor) whose expression, at least in the case of senescence, is strictly p53 dependent.
0008-5472
2404-9
Bond, J.A.
43eecc8a-d00a-43ac-b7d7-d501a0127c91
Blaydes, J. P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Rowson, J.
d4d0231a-131e-41ee-a8b9-046ec13e5d28
Haughton, M. F.
b243337b-f73e-4254-9ec2-b6c513e63ef0
Smith, J. R.
19e43000-8a35-4623-8e88-4106530daa14
Wynford-Thomas, D.
e2abffc0-8c45-4681-b36b-6f1e0fba8ec7
Wyllie, F. S.
91a796eb-05e0-4364-a131-0ebe0f2f5a09
Bond, J.A.
43eecc8a-d00a-43ac-b7d7-d501a0127c91
Blaydes, J. P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Rowson, J.
d4d0231a-131e-41ee-a8b9-046ec13e5d28
Haughton, M. F.
b243337b-f73e-4254-9ec2-b6c513e63ef0
Smith, J. R.
19e43000-8a35-4623-8e88-4106530daa14
Wynford-Thomas, D.
e2abffc0-8c45-4681-b36b-6f1e0fba8ec7
Wyllie, F. S.
91a796eb-05e0-4364-a131-0ebe0f2f5a09

Bond, J.A., Blaydes, J. P., Rowson, J., Haughton, M. F., Smith, J. R., Wynford-Thomas, D. and Wyllie, F. S. (1995) Mutant p53 rescues human diploid cells from senescence without inhibiting the induction of SDI1/WAF1. Cancer Research, 55 (11), 2404-9.

Record type: Article

Abstract

Although the cyclin-dependent kinase inhibitor p21SDI1 (WAF1/CIP1) has been proposed as the mediator of p53-induced cell cycle arrest following DNA damage, several stimuli now appear to induce SDI1 independent of p53 function. We have examined the behavior of p53 and SDI1 in an isogeneic model by manipulating p53 status in normal diploid human fibroblasts using an amphotropic retroviral vector. Following DNA strand break damage induced by bleomycin, both SDI1 induction and G1-S cell cycle arrest are p53 dependent, consistent with SDI1 being the key mediator. In contrast, in cellular senescence (and following UV irradiation), induction of SDI1 occurs independent of p53 function yet growth arrest is still p53 dependent. We conclude (a) that redundant pathways exist for induction of SDI1, but that (b) SDI1, while perhaps necessary, is not sufficient for inhibition of cell cycle progression, requiring the cooperation of an additional factor (possibly another cyclin-dependent kinase inhibitor) whose expression, at least in the case of senescence, is strictly p53 dependent.

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Published date: 1 June 1995

Identifiers

Local EPrints ID: 150587
URI: http://eprints.soton.ac.uk/id/eprint/150587
ISSN: 0008-5472
PURE UUID: b32bf8fa-7535-4745-9f1d-ebd5489ef3f0
ORCID for J. P. Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

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Date deposited: 20 Jul 2010 15:10
Last modified: 23 Jul 2022 01:47

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Contributors

Author: J.A. Bond
Author: J. P. Blaydes ORCID iD
Author: J. Rowson
Author: M. F. Haughton
Author: J. R. Smith
Author: D. Wynford-Thomas
Author: F. S. Wyllie

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