669 publications from this institution
Abstract Phosphoglycerate dehydrogenase (PHGDH) is the metabolic enzyme responsible for shunting the glycolytic intermediate 3-phosphoglycerate to the serine synthesis pathway. In breast cancer and several other types of cancer, increased PHGDH expression is associated with patient mortality. Early studies focused on the role of PHGDH in promoting cell proliferation in the small percentage of breast cancers with PHGDH gene amplification. However, recent studies have revealed a critical role for PHGDH and downstream enzymes of the serine synthesis pathway and one carbon metabolism in NADPH production and the maintenance of redox homeostasis, which are required for enrichment of breast cancer stem cells in response to hypoxia or chemotherapy. These results provide a mechanism for PHGDH overexpression in breast cancers in which PHGDH is not amplified and have implications for improving the response of triple-negative breast cancers to cytotoxic chemotherapy. Cancer Res; 76(22); 6458–62. ©2016 AACR.
Abstract In contrast to Chapters 5 through 12, which described genetic defects involving trans-acting factors that directly bind to DNA and either activate or repress the transcription of target genes, this chapter will focus on disorders involving mutations in genes encoding coactivators, proteins that exert their effects on transcription strictly via protein-protein interactions (see Chapter 3). Coactivators function by establishing physical interactions between sequence-specific DNA-binding proteins and the transcription initiation complex containing Pol II and associated general transcription factors. In addition, many coactivators contain catalytic domains involved in the enzymatic modification of other regulatory proteins or chromatin. Both DNA-binding proteins and coactivators share in common the characteristic that they each regulate only a subset of the Pol II-transcribed sequences in the genome. Whereas the specificity of DNA binding proteins is based on the presence of high-affinity binding-site sequences in proximity to target genes, the specificity of coactivator function must be based in turn on the nature of the DNA-binding proteins that have assembled at regulatory sequences. Because multiple, relatively low-affinity interactions may be involved in determining coactivator interactions, the rules defining coactivator specificity may be more difficult to delineate than those determining DNA-binding activity.
Abstract Red blood cells deliver O2 from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O2-regulated α subunit and a constitutively expressed β subunit. Hydroxylation of HIF-1α or HIF-2α by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1α or HIF-2α by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2α have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.
Hypoxia has long been known to serve as a stimulus for cell cycle arrest. Hypoxia-mediated cell cycle arrest is mediated through the actions of HIF1α (hypoxia inducible factor 1, α subunit [basic helix-loop-helix transcription factor]), which has a nontranscriptional role as an inhibitor of MCM (minichromosome maintenance complex component) helicase activity. We identified chaperone-mediated autophagy as a pathway for selective degradation of HIF1α through lysosomes prior to the onset of DNA replication. CDK2 (cyclin-dependent kinase 2) mediates degradation of HIF1α at the G1/S transition, whereas CDK1 (cyclin-dependent kinase 1) increases HIF1α levels and transcriptional activity prior to the onset of G1 phase. Lysosomal inhibitors induce cell cycle arrest, which is recovered by knockdown of HIF1α and EPAS1/HIF2α. These findings establish lysosomes as essential regulators of cell cycle progression through the degradation of HIF1α.
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates essential homeostatic responses to reduced O2 availability in mammals. Recent studies have provided insights into the O2-dependent regulation of HIF-1 expression, target genes regulated by HIF-1, and the effects of HIF-1 deficiency on cellular physiology and embryonic development.
Abstract Although the nuclear receptor superfamily has an impressive and steadily growing number of members, it represents only a small subset of all known zinc finger transcription factors. Among the dozens of other such factors encoded in the human genome, defects in WTl and GLI3 have been associated with human malformation syndromes and, in the case of WTl, predisposition to tumorigenesis. Germline deletions of chromosome llp13 result in the autosomal dominant WAGR syndrome (MIM 194072), which is characterized by predis position to Wilms tumor, congenital niridia, genitourinary malformations, and mental !:etardation (Riccardi et al., 1978). A contiguous gene syndrome was proposed as the basis for the pleiotropic phenotypic man ifestations (Schmickel, 1986). The predisposition to Wilms tumor (ne phroblastoma) was proposed to be caused by the presence of an inacti vating germline mutation (the llp13 deletion) that was present in all cells of the target organ (the kidney). If tumorigenesis required the in activation of both alleles of a “tumor suppressor” gene within a single cell, then the likelihood of this occurring would be greatly increased by the presence of the first “hit” within all cells of the target organ (Knud son, 1971).
Human cells require O(2) for many metabolic processes, most notably oxidative phosphorylation, the major source of ATP generation, and hypoxia plays a significant pathophysiologic role in a variety of cardiovascular disorders. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of genes whose products, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes, are involved in systemic, local, and cellular responses to hypoxia that either increase O(2) delivery or induce alternative metabolic pathways that do not require O(2). The level of HIF-1 expression in cultured cells is proportional to the degree of hypoxia over the range of O(2) concentrations associated with physiologic and pathophysiologic conditions in vivo. Further investigation of HIF-1 function in vivo may lead to novel therapeutic approaches that modulate cellular responses to hypoxia/ischemia. (Trends Cardiovasc Med 1996;6:151-157).
Abstract Hypoxia-inducible factors (HIFs) were discovered as activators of erythropoietin gene transcription in response to reduced oxygen (O2) availability. O2-dependent hydroxylation of HIFs on proline and asparagine residues regulates protein stability and transcriptional activity, respectively. Mutations in genes encoding components of the O2-sensing pathway cause familial erythrocytosis. Several small-molecule inhibitors of HIF prolyl hydroxylases are currently in clinical trials as erythropoiesis-stimulating agents. HIFs are overexpressed in bone marrow neoplasms, and the development of HIF inhibitors may improve outcomes in these disorders.
