Regulation of E2F in response to DNA damage

Stevens, Craig (2003) Regulation of E2F in response to DNA damage. PhD thesis, University of Glasgow.

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Transcription factor E2F plays in important role in growth control by co-ordinating early cell cycle events. In addition, certain E2F family members, including E2F-1, are endowed with apoptotic activity. E2F-1 is regulated during cell cycle progression and inducible by cellular stress, such as DNA damage. Within the DNA damage signalling pathway, checkpoint kinases act as effectors of the damage response through phosphorylating key substrates involved in growth control. Here, I report that checkpoint kinase Chk2 regulates E2F-1 activity in response to etoposide. A Chk2 kinase phosphorylation site resides in E2F-1, and undergoes physiological phosphorylation in response to DNA damage. Phosphorylation of E2F-1 by Chk2 leads to protein stabilization, increased half-life and transcriptional activation, and phosphorylated E2F-1 resides in discrete nuclear structures. A dominant-negative derivative of Chk2 blocks the induction of E2F-1, and prevents E2F-1-dependent apoptosis. Moreover, E2F-1 fails to be induced by etoposide in tumour cells that carry mutant chk2. Chk2 therefore phosphorylates and activates E2F-1 in the cellular response to DNA damage, and the damage induction of E2F-1 leads to apoptosis. The results suggest a role for E2F-1 in response to stress, perhaps in checkpoint control, and provide a plausible mechanistic and physiological explanation for the tumour suppressor activity of E2F-1.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QH Natural history > QH345 Biochemistry
Q Science > QR Microbiology
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: La Thangue, Prof. Nicholas B.
Date of Award: 2003
Depositing User: Miss Louise Annan
Unique ID: glathesis:2003-6547
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jul 2015 09:26
Last Modified: 15 Jul 2015 10:28

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