E2F3a functions as an oncogene and induces DNA damage response pathway mediated apoptosis


E2F3a functions as an oncogene and induces DNA damage response pathway mediated apoptosis

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dc.contributor.advisor Johnson, David, 1963-
dc.contributor.advisor Bratton, Shawn B.
dc.creator Paulson, Qiwei Xia, 1974-
dc.date.accessioned 2008-08-28T23:44:56Z
dc.date.available 2008-08-28T23:44:56Z
dc.date.created 2007
dc.date.issued 2008-08-28T23:44:56Z
dc.identifier.uri http://hdl.handle.net/2152/3390
dc.description.abstract Mutation or inactivation of RB occurs in most human tumors and results in the deregulation of several E2F family transcription factors. Among the E2F family, E2F3 has been implicated as a key regulator of cell proliferation and E2f3 gene amplification and overexpression is detected in some human tumors. To study the role of E2F3a in tumor development, we established a transgenic mouse model expressing E2F3a in a number of epithelial tissues via a keratin 5 (K5) promoter. Transgenic expression of E2F3a leads to hyperproliferation, hyperplasia and increased levels of p53-independent apoptosis in transgenic epidermis. Consistent with data from human cancers, the E2f3a transgene is found to have a weak oncogenic activity on its own and to enhance the response to a skin carcinogenesis protocol. While E2F3a induces apoptosis in the absence of p53, the inactivation of both p53 and p73, but not p73 alone, significantly impairs apoptosis induced by E2F3a. This suggests that both p53 and p73 contribute to E2F3a induced apoptosis but that their function is compensatory. Even though data suggest that E2F3a carries out its unique apoptotic activity in part through another E2F family member E2F1, unlike E2F1, the ARF tumor suppressor is required for E2F3a-induced apoptosis. While both E2F3a and E2F1 require ATM for apoptosis, E2F3a activates ATM through a distinct mechanism from E2F1. The overexpression of E2F3a results in the accumulation of DNA damage in K5 transgenic keratinocytes and normal human fibroblasts (NHFs). In response to this, the DNA damage checkpoint kinase ATM is activated, and phosphorylation of the downstream targets p53 and the histone variant H2AX are significantly increased. Additional studies show that increased Cdk activity and aberrant DNA replication contributes to DNA damage, ATM activation and apoptosis in response to deregulated E2F3a, which suggest that aberrant replication imposed by deregulated E2F3a plays an important role in the activation of the ATM DNA damage response pathway. Activation of ATM by E2F3a is not affected by loss of ARF or E2F1. Meanwhile, E2F3a-induced ARF upregulation is not affected by E2F1 loss. The above results indicate that E2F3a engages several parallel pathways involving E2F1, ARF and the ATM kinase, and these pathways cooperate to promote apoptosis.
dc.format.medium electronic
dc.language.iso eng
dc.rights Copyright © is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.
dc.subject.lcsh Oncogenes
dc.subject.lcsh Carcinogenesis
dc.subject.lcsh Apoptosis
dc.subject.lcsh DNA damage
dc.subject.lcsh Skin--Cancer--Genetic aspects
dc.subject.lcsh Transcription factors
dc.title E2F3a functions as an oncogene and induces DNA damage response pathway mediated apoptosis
dc.description.department Pharmacy
dc.identifier.oclc 180277025
dc.identifier.recnum b69270971
dc.type.genre Thesis
dc.type.material text
thesis.degree.department Pharmacy
thesis.degree.discipline Pharmacy
thesis.degree.grantor The University of Texas at Austin
thesis.degree.level Doctoral
thesis.degree.name Doctor of Philosophy

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