Browsing by Subject "Heat shock transcription factors"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats
    (Elsevier, 2013) Basile, David P.; Dwinell, Melinda R.; Wang, Shur-Jen; Shames, Brian D.; Donohoe, Deborah; Chen, Shaoying; Sreedharan, Rajasree; Van Why, Scott K.; Cellular and Integrative Physiology, School of Medicine
    Brown Norway rats (BN, BN/NHsdMcwi) are profoundly resistant to developing acute kidney injury (AKI) following ischemia reperfusion. To help define the genetic basis for this resistance, we used consomic rats, in which individual chromosomes from BN rats were placed into the genetic background of Dahl SS rats (SS, SS/JrHsdMcwi) to determine which chromosomes contain alleles contributing to protection from AKI. The parental strains had dramatically different sensitivity to ischemia reperfusion with plasma creatinine levels following 45 min of ischemia and 24 h reperfusion of 4.1 and 1.3 mg/dl in SS and BN, respectively. No consomic strain showed protection similar to the parental BN strain. Nine consomic strains (SS-7(BN), SS-X(BN), SS-8(BN), SS-4(BN), SS-15(BN), SS-3(BN), SS-10(BN), SS-6(BN), and SS-5(BN)) showed partial protection (plasma creatinine about 2.5-3.0 mg/dl), suggesting that multiple alleles contribute to the severity of AKI. In silico analysis was performed using disease ontology database terms and renal function quantitative trait loci from the Rat Genome Database on the BN chromosomes giving partial protection from AKI. This tactic identified at least 36 candidate genes, with several previously linked to the pathophysiology of AKI. Thus, natural variants of these alleles or yet-to-be identified alleles on these chromosomes provide protection against AKI. These alleles may be potential modulators of AKI in susceptible patient populations.
  • Thumbnail Image
    Item
    HSF1 Inhibits Antitumor Immune Activity in Breast Cancer by Suppressing CCL5 to Block CD8+ T-cell Recruitment
    (American Association for Cancer Research, 2024) Jacobs, Curteisha; Shah, Sakhi; Lu, Wen-Cheng; Ray, Haimanti; Wang, John; Hockaden, Natasha; Sandusky, George; Nephew, Kenneth P.; Lu, Xin; Cao, Sha; Carpenter, Richard L.; Pathology and Laboratory Medicine, School of Medicine
    Heat shock factor 1 (HSF1) is a stress-responsive transcription factor that promotes cancer cell malignancy. To provide a better understanding of the biological processes regulated by HSF1, here we developed an HSF1 activity signature (HAS) and found that it was negatively associated with antitumor immune cells in breast tumors. Knockdown of HSF1 decreased breast tumor size and caused an influx of several antitumor immune cells, most notably CD8+ T cells. Depletion of CD8+ T cells rescued the reduction in growth of HSF1-deficient tumors, suggesting HSF1 prevents CD8+ T-cell influx to avoid immune-mediated tumor killing. HSF1 suppressed expression of CCL5, a chemokine for CD8+ T cells, and upregulation of CCL5 upon HSF1 loss significantly contributed to the recruitment of CD8+ T cells. These findings indicate that HSF1 suppresses antitumor immune activity by reducing CCL5 to limit CD8+ T-cell homing to breast tumors and prevent immune-mediated destruction, which has implications for the lack of success of immune modulatory therapies in breast cancer. Significance: The stress-responsive transcription factor HSF1 reduces CD8+ T-cell infiltration in breast tumors to prevent immune-mediated killing, indicating that cellular stress responses affect tumor-immune interactions and that targeting HSF1 could improve immunotherapies.
  • Thumbnail Image
    Item
    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.