Steven Berberich (Committee Member), Thomas Brown (Committee Member), Paula Bubulya (Committee Member), Madhavi Kadakia (Advisor), Michael Leffak (Committee Member)
Doctor of Philosophy (PhD)
Non-melanoma skin cancers (NMSCs) are the most common form of cancer in the United States with an estimated 3.5 million new cases each year. Surgical excision is the main treatment for NMSC, but leaves the potential for disfiguring scars and does not fully reduce the risk of recurrence since the surrounding tissue is also sun damaged and may contain tumor-promoting mutations. By understanding the molecular etiology of NMSC we may be able to expand treatment options to more than just resection. Normal epidermal development is dependent upon the expression of the transcription factor p63. Amplification of the ΔNp63α isoform is also frequently observed in NMSC, making it an excellent candidate for understanding the etiology of NMSC.
This dissertation focuses on how ΔNp63α influences keratinocyte proliferation by regulating phosphatase and tensin homologue deleted on chromosome ten (PTEN). The tumor suppressor PTEN has been called "the second guardian of the genome" for its widespread role in preventing tumor formation and is second only to p53 in the frequency of observed mutations or loss in human cancers. The studies presented in this dissertation demonstrate that ΔNp63α is able to maintain the proliferative potential of keratinocytes by activating Akt through transcriptional repression of PTEN. The inhibition of PTEN by ΔNp63α was independent of any repressive effects of ΔNp63α towards other p53 family members. Since the discovery of nuclear PTEN the tumor suppressive functions of PTEN have expanded to include induction of cell cycle arrest, accentuation of apoptotic signaling and maintenance of chromosome stability. ΔNp63α was also shown to inhibit the nuclear localization of PTEN, which may further the increase the proliferative potential of basal layer keratinocytes. Inhibition of NEDD4-1 by ΔNp63α was implicated in reducing the ubiquitination of PTEN, thereby preventing its import into the nucleus. The studies presented here also identify a novel pool of PTEN that is localized to centrosomes only during mitosis. Coordinated control of both Akt and PTEN regulate centrosome composition and integrity during mitosis and provides insight into how PTEN functions as a multifaceted tumor suppressor. The importance of the ΔNp63α/PTEN/Akt signaling loop in epidermal biology was highlighted by the significant disruption of ΔNp63α and PTEN levels in NMSC. Altogether, these studies provide important molecular insight into the control of keratinocyte proliferation by the ΔNp63α-PTEN-Akt signaling loop.
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