| dc.contributor.advisor |
Johnson , David , 1963 - |
en_US |
| dc.contributor.advisor |
Bratton , Shawn B . |
en_US |
| dc.identifier.oclc |
180277025 |
en_US |
| dc.creator |
Paulson , Qiwei Xia , 1974 - |
en_US |
| dc.date.accessioned |
2008 -08 -28T23 :44 :56Z |
|
| dc.date.available |
2008 -08 -28T23 :44 :56Z |
|
| dc.date.created |
2007 |
en_US |
| 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 . |
en_US |
| dc.format.medium |
electronic |
en_US |
| dc.language.iso |
eng |
en_US |
| 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 . |
en_US |
| dc.subject.lcsh |
Oncogenes |
en_US |
| dc.subject.lcsh |
Carcinogenesis |
en_US |
| dc.subject.lcsh |
Apoptosis |
en_US |
| dc.subject.lcsh |
DNA damage |
en_US |
| dc.subject.lcsh |
Skin - -Cancer - -Genetic aspects |
en_US |
| dc.subject.lcsh |
Transcription factors |
en_US |
| dc.title |
E2F3a functions as an oncogene and induces DNA damage response pathway mediated apoptosis |
en_US |
| dc.description.department |
Pharmacy |
en_US |
| dc.identifier.recnum |
b69270971 |
en_US |
| dc.type.genre |
Thesis |
en_US |
| dc.type.material |
text |
en_US |
| thesis.degree.name |
Doctor of Philosophy |
en_US |
| thesis.degree.level |
Doctoral |
en_US |
| thesis.degree.discipline |
Pharmacy |
en_US |
| thesis.degree.grantor |
The University of Texas at Austin |
en_US |
| thesis.degree.department |
Pharmacy |
en_US |