Molecular mechanisms of cellular response to hypoxia

Abstract

Hypoxia is a reduction in the normal level of tissue oxygen tension, which occurs in human living at high altitude, during embryonic and fetal development and commonly in a variety of acute and chronic vascular, pulmonary, and neoplastic diseases. The identification of the master transcriptional regulator in response to hypoxia (hypoxia inducible factor-1, HIF-1) and the revelation of the molecular oxygen sensing mechanisms by prolyl hydroxylases domain (PHD) proteins expanded immensely the understanding of the cellular response to hypoxia. Based on our observation that HIF-1 signaling occurs in the leukemic bone marrow of childhood acute lymphoblastic leukemia (ALL), this PhD-thesis focuses on the identification of new oxygen regulated target genes either involving HIF-1 (Histone demethylase Jumonji domain containing 1A, JMJD1A, and Wilms’ tumor suppressor 1, Wt1) or alternative mechanisms (RNA binding motif protein 3, RBM3, and cold inducible RNA-binding protein, CIRP). We characterize the function of these HIF-1 dependent and independent target genes in respect to cellular adaptation to hypoxia, their tissue specific role, and their implications in diseases. The studies presented here have contributed 1) to a deeper and better understanding of the adaptation of leukemic cells to the bone marrow microenvironment, 2) to the identification of genes involved in epigenetic processes (JMJD1A) and cell survival (WT1) in response to decreased oxygen tension mediated by HIF-1, 3) to the identification of genes (RBM3 and CIRP), which are up-regulated by decreased oxygen tension via an alternative signaling mechanism not involving the master transcriptional regulator in response to hypoxia, and 4) to the characterization of RBM3 as a new survival protein protecting cells from adverse growth conditions such as serum deprivation-induced cell death.