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

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Title: E2F3a functions as an oncogene and induces DNA damage response pathway mediated apoptosis
Author: Paulson, Qiwei Xia, 1974-
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 .
URI: http : / /hdl .handle .net /2152 /3390
Date: 2008-08-28

Citation

E2F3a functions as an oncogene and induces DNA damage response pathway mediated apoptosis. Doctoral dissertation, The University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /3390 .

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