Browsing by Author "Williams, Imade"

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    AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation
    (Wiley, 2022) Lu, Wen-Cheng; Omari, Ramsey; Ray, Haimanti; Wang, John; Williams, Imade; Jacobs, Curteisha; Hockaden, Natasha; Bochman, Matthew L.; Carpenter, Richard L.; Biochemistry and Molecular Biology, School of Medicine
    The heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activation requires nuclear localization, trimerization, DNA binding, phosphorylation and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, MEK1 and DYRK2. Here, we observed activation of HSF1 by AKT1 independently of mTOR. AKT2 also phosphorylated S326 of HSF1 but showed weak ability to activate HSF1. Similarly, mTOR, p38, MEK1 and DYRK2 all phosphorylated S326 but AKT1 was the most potent activator. Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. Interestingly, T527 as a phosphorylated residue has not been previously shown and sits in the transactivation domain, further implying a role for this site in HSF1 gene transactivation. This study suggests that HSF1 hyperphosphorylation is targeted and these specific residues have direct function in regulating HSF1 transcriptional activity.
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    MYC and HSF1 Cooperate to Drive Sensitivity to Polo-like Kinase 1 Inhibitor Volasertib in High-grade Serous Ovarian Cancer
    (American Association for Cancer Research, 2025) Williams, Imade; O’Malley, Matthew; DeHart, Haddie; Walker, Bobby; Ulhaskumar, Vrushabh; Jothirajah, Pranav; Ray, Haimanti; Landrum, Lisa M.; Delaney, Joe R.; Nephew, Kenneth P.; Carpenter, Richard L.; Obstetrics and Gynecology, School of Medicine
    We show that HSF1 and MYC genes are co-amplified in more than 30% of HGSOC and demonstrate that HSF1 and MYC functionally cooperate to drive the growth of HGSOC cells. This work provides the foundation for HSF1 and MYC co-amplification as a biomarker for treatment efficacy of the polo-like kinase 1 inhibitor volasertib in HGSOC.