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Andrew Jared Stacy Dissertation.pdf (4.1 MB)

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Regulation of ΔNp63α by TIP60 promotes cellular proliferation

Stacy, Andrew Jared
http://orcid.org/0000-0002-7528-2810
http://rave.ohiolink.edu/etdc/view?acc_num=wright1596151919161674

Abstract Details

2020, Doctor of Philosophy (PhD), Wright State University, Biomedical Sciences PhD.
ΔNp63α is a p53 transcription factor family member that promotes cellular proliferation and survival. In squamous cell carcinoma (SCC), ΔNp63α overexpression is associated with poor prognosis and survival, implicating it as a proto-oncogene. Despite its importance in SCC, the mechanisms regulating ΔNp63α expression are poorly understood. We have identified the acetyltransferase TIP60 as a novel upstream regulator of ΔNp63α levels. We discovered that TIP60 regulates ΔNp63α via two mechanisms. First, TIP60 upregulates ΔNp63α mRNA levels. Moreover, pharmacological inhibition of TIP60 activity reduces ΔNp63α transcript levels, indicating that TIP60-cataltyic activity is vital to amplified transcription of ΔNp63α. Second, we have demonstrated that TIP60 promotes ΔNp63α protein stability by preventing its ubiquitination and proteasomal degradation. This study further shows that TIP60 co-localizes with, interacts with, and directly acetylates ΔNp63α. Utilizing mass spectrometry and site directed mutagenesis, we found that TIP60 acetylates ΔNp63α residues K138, K139, and K494, respectively. We additionally revealed that preventing acetylation of these sites inhibit TIP60-mediated stabilization of ΔNp63α, providing evidence that acetylation by TIP60 enhances ΔNp63α protein stability. We further investigated the functions of the TIP60-ΔNp63α axis in the regulation of SCC proliferation. We discovered that regulation of ΔNp63α by TIP60 increases cellular proliferation. In accordance with the functional role of ΔNp63α, pharmacological inhibition of TIP60 reduced SCC cell proliferation suggesting TIP60 may have therapeutic potential in cancers exhibiting ΔNp63α overexpression. Furthermore, we investigated the mechanisms by which TIP60 regulation of ΔNp63α enhances cancer cell proliferation. We discovered that TIP60 upregulation of ΔNp63α represses p21Cip1/Waf1 levels, resulting in increased G2/M progression. In conclusion, this study uncovers a novel mechanism promoting ΔNp63α-mediated cellular proliferation in SCC. These findings may be critical for designing new therapeutic strategies for the treatment of SCC by targeting ΔNp63α expression and activity.
Madhavi Kadakia, Ph.D. (Advisor)
Thomas L. Brown, Ph.D. (Committee Chair)
Paula A. Bubulya, Ph.D. (Committee Member)
Weiwen Long, Ph.D. (Committee Member)
Michael P. Markey, Ph.D. (Committee Member)
155 p.
Biochemistry; Biomedical Research; Cellular Biology; Molecular Biology; Oncology
p63; TIP60; acetylation; p21; cell proliferation; cell cycle; cancer; non-melanoma skin cancer; squamous cell carcinoma

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Citations

  • Stacy, A. J. (2020). Regulation of ΔNp63α by TIP60 promotes cellular proliferation [Doctoral dissertation, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1596151919161674

    APA Style (7th edition)

  • Stacy, Andrew. Regulation of ΔNp63α by TIP60 promotes cellular proliferation. 2020. Wright State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1596151919161674.

    MLA Style (8th edition)

  • Stacy, Andrew. "Regulation of ΔNp63α by TIP60 promotes cellular proliferation." Doctoral dissertation, Wright State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1596151919161674

    Chicago Manual of Style (17th edition)

wright1596151919161674
222
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This open access ETD is published by Wright State University and OhioLINK.