C/EBP-alpha is an epithelial tumor suppressor gene, and mitogenic stimulation reciprocally regulates C/EBP-alpha and C/EBP-beta

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dc.contributor.advisor Robert C. Smart, Committee Chair en_US
dc.contributor.advisor Barbara Sherry, Committee Member en_US
dc.contributor.advisor David Bird, Committee Member en_US
dc.contributor.advisor Marcelo L. Rodriguez-Puebla, Committee Member en_US
dc.contributor.author Loomis, Kari Danielle en_US
dc.date.accessioned 2010-04-02T19:06:50Z
dc.date.available 2010-04-02T19:06:50Z
dc.date.issued 2008-11-09 en_US
dc.identifier.other etd-07102008-104359 en_US
dc.identifier.uri http://www.lib.ncsu.edu/resolver/1840.16/5059
dc.description.abstract CCAAT/enhancer binding protein α (C/EBPα) and C/EBPβ are basic leucine zipper transcription factors that function in the inhibition and stimulation of cell cycle progression, and regulate differentiation in various cell types. C/EBPα is inactivated by mutation in acute myeloid leukemia (AML) and is considered a human tumor suppressor in AML. While C/EBPα mutations have not been observed in malignancies other than AML, greatly diminished expression of C/EBPα occurs in numerous human epithelial cancers including those of lung, liver, endometrium, skin and breast suggesting a possible tumor suppressor function. However, direct evidence for C/EBPα as an epithelial tumor suppressor is lacking due to the absence of C/EBPα mutations in epithelial tumors and the lethal effect of C/EBPα deletion in mouse model systems. To examine the function of C/EBPα in epithelial tumor development, an epidermal-specific C/EBPα knockout mouse was generated. The epidermal-specific C/EBPα knockout mice survived and displayed no detectable abnormalities in epidermal keratinocyte proliferation, differentiation or apoptosis; demonstrating that C/EBPα is dispensable for normal epidermal homeostasis. In spite of this, the epidermal-specific C/EBPα knockout mice were highly susceptible to skin tumor development involving oncogenic Ras. These mice displayed decreased tumor latency and striking increases in tumor incidence, multiplicity, growth rate and the rate of malignant progression. Mice hemizygous for C/EBPα displayed an intermediate enhanced tumor phenotype. Our results suggest decreased expression of C/EBPα contributes to deregulation of tumor cell proliferation. C/EBPα had been proposed to block cell cycle progression through inhibition of E2F activity. We observed that C/EBPα blocked Ras-induced and epidermal growth factor–induced E2F activity in keratinocytes and also blocked Ras-induced cell transformation and cell cycle progression. Next the effects of mitogenic stimulation on C/EBPα and C/EBPβ expression were studied. Stimulation of cells in culture with EGF resulted in decreased C/EBPα expression, as well as a reciprocal increase in C/EBPβ expression. Further, loss of C/EBPβ results in an inhibited transition from the G1 to S phase of the cell cycle after treatment with EGF, and this reduction was associated with decreased expression of E2F target genes. Both C/EBPα and C/EBPβ have been proposed to affect cell cycle progression through interactions with E2F. We observed that C/EBPα blocked while C/EBPβ stimulated Ras- and EGF-induced E2F activity in keratinocytes. My results demonstrate that C/EBPα is dispensable for epidermal homeostasis, that C/EBPα and C/EBPβ are reciprocally regulated by mitogenic stimulation, and provide genetic evidence that C/EBPα is a haploinsufficent suppressor gene in epithelial tumorigenesis. en_US
dc.rights I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dis sertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. en_US
dc.subject cancer en_US
dc.subject C/EBP en_US
dc.subject cell cycle en_US
dc.subject keratinocytes en_US
dc.title C/EBP-alpha is an epithelial tumor suppressor gene, and mitogenic stimulation reciprocally regulates C/EBP-alpha and C/EBP-beta en_US
dc.degree.name PhD en_US
dc.degree.level dissertation en_US
dc.degree.discipline Functional Genomics en_US

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