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HGF/Met-mediated Phosphorylation of Stathmin1 Serine 16 Regulates Cell Proliferation and not Metastasis

Deford, Paul
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1659535396707629

Abstract Details

2022, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
The focus of this dissertation is Hepatocyte Growth Factor (HGF)/MET-mediated phosphorylation of STMN1 on Serine 16 and the impact on cell cycle progression and cell proliferation. While the treatment of low-grade prostate cancers (PCa) with androgen deprivation therapy (ADT) often eliminates androgen receptor (AR)+ bulk tumor cells, 20-30% of the men treated will eventually develop castration resistant prostate cancer (CRPC). Of note is that AR normally represses the transcription of the HGF receptor MET, and that prolonged therapy can downregulate AR expression, resulting in a corresponding increase in MET expression, reported to be an indicator of late stage PCa and poor overall survival. Progression to late stage PCa is also characterized by an increased production and secretion of HGF from cells within the tumor microenvironment (TME) to upregulate metastatic and proliferative cellular processes. In this dissertation, Chapter 1 provides context regarding the role of the TME in cancer development, progression, and therapeutic resistance; and a brief summary of the current understanding of HGF/MET signaling in cancer and its role in STMN1 phosphorylation. Chapter 2 presents novel findings regarding HGF/MET-mediated phosphorylation of STMN1 S16 and how this modulates cell cycle progression, proliferation and metastatic potential in both PCa cells and normal mouse mammary gland cells. Chapter 3 investigates how calcium/calmodulin-dependent protein kinase II (CAMKII) regulates PCa cell proliferation without triggering metastasis, and the role that the other three regulatory serines in STMN1 play in regulating PCa cell proliferation. Chapter 4 reports the role of constant degradation of AR by Mouse Double Minute 2 (MDM2) to maintain prostate cancer stem cell integrity. Chapter 5 provides an in-depth analysis of the advantages and challenges faced in our attempt to use CRISPR/Cas9 technology to generate stable iii mutant DU-145 cell lines expressing STMN1 substitution mutations. Finally, Chapter 6 discusses the overall conclusions of the dissertation and provides future directions for further study. For the first time, we demonstrate HGF/MET signaling phosphorylates STMN1 on S16 to promote cell cycle progression through the shortening of cell-doubling time, resulting in an increase in cellular proliferation. We also demonstrate that differential phosphorylation of the other three regulatory serines of STMN1 do not play a significant role in the regulation of cell cycle progression and cell proliferation. The Kasper Laboratory previously published that downregulation of total STMN1 resulted in an inhibition of proliferation and an induction of metastasis. Herein, we show, for the first time, that HGF/MET-mediated phosphorylation of STMN1 S16 does not induce metastasis. Finally, we provide evidence in support of a novel therapeutic strategy of utilizing the potent c-MET inhibitor AMG337 in combination with ADT to decrease or eliminate the development of late-stage PCa and metastasis.
Susan Kasper, Ph.D. (Committee Member)
Susan Waltz, Ph.D. (Committee Member)
Saulius Sumanas, Ph.D. (Committee Member)
Katherine Burns, Ph.D. (Committee Member)
183 p.
Cellular Biology
cancer therapy; HGF/MET signaling; HGF; Stathmin; cell cycle progression; cell proliferation

Recommended Citations

Citations

  • Deford, P. (2022). HGF/Met-mediated Phosphorylation of Stathmin1 Serine 16 Regulates Cell Proliferation and not Metastasis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1659535396707629

    APA Style (7th edition)

  • Deford, Paul. HGF/Met-mediated Phosphorylation of Stathmin1 Serine 16 Regulates Cell Proliferation and not Metastasis. 2022. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1659535396707629.

    MLA Style (8th edition)

  • Deford, Paul. "HGF/Met-mediated Phosphorylation of Stathmin1 Serine 16 Regulates Cell Proliferation and not Metastasis." Doctoral dissertation, University of Cincinnati, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1659535396707629

    Chicago Manual of Style (17th edition)

ucin1659535396707629
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This open access ETD is published by University of Cincinnati and OhioLINK.