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Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways

Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways
Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways
High level activation of p53-dependent transcription occurs following cellular exposure to genotoxic damaging agents such as UV-C, while ionizing radiation damage does not induce a similarly potent induction of p53-dependent gene expression. Reasoning that one of the major differences between UV-C and ionizing radiation damage is that the latter does not inhibit general transcription, we attempted to reconstitute p53-dependent gene expression in ionizing irradiated cells by co-treatment with selected transcription inhibitors that alone do not activate p53. p53-dependent transcription can be dramatically enhanced by the treatment of ionizing irradiated cells with low doses of DRB, which on its own does not induce p53 activity. The mechanism of ionizing radiation-dependent activation of p53-dependent transcription using DRB is more likely due to inhibition of gene transcription rather than prolonged DNA damage, as the non-genotoxic and general transcription inhibitor Roscovitine also synergistically activates p53 function in ionizing irradiated cells. These results identify two distinct signal transduction pathways that cooperate to fully activate p53-dependent gene expression: one responding to lesions induced by ionizing radiation and the second being a kinase pathway that regulates general RNA Polymerase II activity.
0950-9232
3829-3839
Blaydes, J. P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Craig, A. L.
58c10c58-e22f-454d-abac-f22b38d91a06
Wallace, M.
78438244-57f6-43d7-8aec-5b345cd2de31
Ball, H. M.
87836960-4528-4f99-97bd-1f4a37eaede2
Traynor, N. J.
7606ac6c-b35c-4343-89a8-4ea2b6141aa3
Gibbs, N. K.
0dcd23ee-aa76-4f3f-b4a0-7f638283d35a
Hupp, T. R.
103f5e92-932d-4d91-84f7-906c16b31321
Blaydes, J. P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Craig, A. L.
58c10c58-e22f-454d-abac-f22b38d91a06
Wallace, M.
78438244-57f6-43d7-8aec-5b345cd2de31
Ball, H. M.
87836960-4528-4f99-97bd-1f4a37eaede2
Traynor, N. J.
7606ac6c-b35c-4343-89a8-4ea2b6141aa3
Gibbs, N. K.
0dcd23ee-aa76-4f3f-b4a0-7f638283d35a
Hupp, T. R.
103f5e92-932d-4d91-84f7-906c16b31321

Blaydes, J. P., Craig, A. L., Wallace, M., Ball, H. M., Traynor, N. J., Gibbs, N. K. and Hupp, T. R. (2000) Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways. Oncogene, 19 (34), 3829-3839.

Record type: Article

Abstract

High level activation of p53-dependent transcription occurs following cellular exposure to genotoxic damaging agents such as UV-C, while ionizing radiation damage does not induce a similarly potent induction of p53-dependent gene expression. Reasoning that one of the major differences between UV-C and ionizing radiation damage is that the latter does not inhibit general transcription, we attempted to reconstitute p53-dependent gene expression in ionizing irradiated cells by co-treatment with selected transcription inhibitors that alone do not activate p53. p53-dependent transcription can be dramatically enhanced by the treatment of ionizing irradiated cells with low doses of DRB, which on its own does not induce p53 activity. The mechanism of ionizing radiation-dependent activation of p53-dependent transcription using DRB is more likely due to inhibition of gene transcription rather than prolonged DNA damage, as the non-genotoxic and general transcription inhibitor Roscovitine also synergistically activates p53 function in ionizing irradiated cells. These results identify two distinct signal transduction pathways that cooperate to fully activate p53-dependent gene expression: one responding to lesions induced by ionizing radiation and the second being a kinase pathway that regulates general RNA Polymerase II activity.

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Published date: 10 August 2000

Identifiers

Local EPrints ID: 150551
URI: https://eprints.soton.ac.uk/id/eprint/150551
ISSN: 0950-9232
PURE UUID: 15a696fa-10d7-4c37-a397-139db6bfb36a
ORCID for J. P. Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

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Date deposited: 20 Jul 2010 10:48
Last modified: 18 May 2019 00:36

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Contributors

Author: J. P. Blaydes ORCID iD
Author: A. L. Craig
Author: M. Wallace
Author: H. M. Ball
Author: N. J. Traynor
Author: N. K. Gibbs
Author: T. R. Hupp

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