Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Prostate cancer is one of the most common malignancies and causes of cancer related death in men. Morbidity is primarily attributed to late-stage and metastatic disease. Re-cent genomic screening studies have revealed that the Speckle type Poz Protein (SPOP) is the most frequently altered gene by missense mutations in prostate cancer. Interestingly, all of the identified mutations were located in the substrate binding domain of SPOP. Here, two pathways highlighting the impact of SPOP mutation on prostate cancer are pre-sented. First, evidence showing that one of the naturally occurring SPOP mutations, ser-ine 119 to asparagine (S119N), induces radiosensitivity and an apparent defect in the DNA Damage Response (DDR). The S119N mutant SPOP causes prolonged DNA re-pair, ineffective cell cycle checkpoints and reduced viability in response to ionizing radia-tion. Further, biochemical analysis of the functional significance of serine 119 demon-strated that it is required for radiation induced SPOP-ATM (Ataxia Telangiectasia) inter-action. This is further validated by studies indicating that ATM, a critical mediator of the DNA damage response, is required for radiation induced serine 119 phosphorylation. In sum, the evidence shows that ATM phosphorylation of SPOP on serine 119 is a critical step in the DDR. Second, a clinical cohort of prostate cancer patients was analyzed and it was observed that SPOP mutation is an independent predictor of metastasis. Via proteo-mic analysis candidate proteins for SPOP regulation that also play a role in metastasis were identified. It is demonstrated that SPOP interacts with and regulates ITCH protein levels. Further, the data indicates that SPOP mutation interrupts SPOP ITCH binding and leads to a subsequent accumulation of ITCH protein. Lastly, evidence demonstrated that increases in ITCH due to mutation in SPOP results in a concurrent loss of E-cadherin pro-tein expression. Together are presented two clinically relevant SPOP-dependent pathways that impact prostate cancer initiation and progression.
Fried, Joshua, "Identification Of Two Spop-Mediated Pathways In Prostate Cancer Progression" (2019). All ETDs from UAB. 1671.