Browsing by Subject "Hypoxia-Inducible Factor 1, alpha Subunit"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    HIF-transcribed p53 chaperones HIF-1α
    (Oxford University Press, 2019-11-04) Madan, Esha; Parker, Taylor M.; Pelham, Christopher J.; Palma, Antonio M.; Peixoto, Maria L.; Nagane, Masaki; Chandaria, Aliya; Tomás, Ana R.; Canas-Marques, Rita; Henriques, Vanessa; Galzerano, Antonio; Cabral-Teixeira, Joaquim; Selvendiran, Karuppaiyah; Kuppusamy, Periannan; Carvalho, Carlos; Beltran, Antonio; Moreno, Eduardo; Pati, Uttam K.; Gogna, Rajan; Surgery, School of Medicine
    Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.
  • Thumbnail Image
    Item
    Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment
    (American Society of Hematology, 2014-01-09) Speth, Jennifer M.; Hoggatt, Jonathan; Singh, Pratibha; Pelus, Louis M.; Department of Microbiology and Immunology, IU School of Medicine
    Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of immunologic disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl prostaglandin E2 (dmPGE2). While exploring regulatory molecules involved in dmPGE2 enhancement, we found that transiently increasing the transcription factor hypoxia-inducible factor 1-α (HIF1α) is required for dmPGE2-enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells and that pharmacologic manipulation of HIF1α is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE2 enhances the function of hematopoietic stem and progenitor cells; these data also define a role for hypoxia and HIF1α in enhancement of hematopoietic transplantation.