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LIMK2-UBE2C SYNERGY DRIVES CASTRATION-RESISTANT PROSTATE CANCER AND CDK5-CYCLIN B1 REGULATES MITOTIC PROGRESSION AND FIDELITY

thesis
posted on 2024-04-26, 01:34 authored by Humphrey L LotanaHumphrey L Lotana

UBE2C is upregulated in castration-resistant prostate cancer and shows strong correlation with high tumor grade. Currently, the scarcity of UBE2C inhibitors is alarming. This study is the first to report UBE2C post-translational modulation mediated by LIMK2 kinase. A proteome-wide screen previously conducted in the Shah lab has identified UBE2C as a direct substrate of LIMK2 using an innovative chemical genetic approach. LIMK2 regulates UBE2C in a variety of ways. First, LIMK2 directly associates with UBE2C in cells. Second, LIMK2 phosphorylates UBE2C at S123 and increases its stability at the protein level. Third, LIMK2 upregulates UBE2C mRNA and protein expression levels in cells. Contrary to its well-established function as an enzyme involved in the ubiquitin-proteosome pathway, UBE2C stabilizes LIMK2 protein expression in a reciprocal loop. This study is the first to show UBE2C stabilizing its substrate. Likewise, UBE2C increases LIMK2 mRNA and protein levels; however, the mechanism is to be elucidated. LIMK2-UBE2C loop is extremely oncogenic creating CRPC pathogenesis in vivo. Targeting LIMK2 is a suitable approach to effectively degrade both UBE2C and LIMK2 which leads to significant inhibition of tumor formation, cancer stem cell phenotype and epithelial to mesenchymal transition in vivo. Additionally, CDK1 for the longest time was thought to be the only protein of the cyclin dependent kinase family which binds to and is activated by cyclin B1 to regulate cell cycle progression. We first showed CDK5 activity in cell division and its importance in maintaining mitotic fidelity. We first established the activation of CDK5 by cyclin B1 in vitro. The phospho-mimetic CDK5 was observed to be less active when bound to cyclin B1 than its wild-type counterpart.

History

Degree Type

  • Doctor of Philosophy

Department

  • Chemistry

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Scott McLuckey

Additional Committee Member 2

Chittaranjan Das

Additional Committee Member 3

Shalini Low-Nam

Additional Committee Member 4

Shiliang Tian

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