title: Golgi Associated HIF1a Serves as a Reserve in Melanoma Cells.
abstract: Hypoxia-inducible factor-1alpha (HIF1a) is a key transcriptional regulator that enables cellular metabolic adaptation to low levels of oxygen. Multiple mechanisms, including lysosomal degradation, control the levels of HIF1a protein. Here we show that HIF1a protein degradation is resistant to lysosomal inhibition and that HIF1a is associated with the Golgi compartment in melanoma cells. Although pharmacological inhibitors of prolyl hydroxylation, neddylation and the proteasome inhibited degradation of HIF1a, attenuation of lysosomal activity with chloroquine did not alter the levels of HIF1a or its association with Golgi. Pharmacological disruption of Golgi resulted in nuclear accumulation of HIF1a. However, blockade of ER-Golgi protein transport in hypoxia reduced the transcript levels of HIF1a target genes. These findings suggest a possible role for the oxygen-dependent protein folding process from the ER-Golgi compartment in fine-tuning HIF1a transcriptional output.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, 46202.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lakhter
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202.
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
authors.affiliation: Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, Indiana, 46202.
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, 46202.
authors.forename: Samisubbu R
authors.initials: SR
authors.lastname: Naidu
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000494:pharmacology*; D064828:Prolyl Hydroxylases / Q000235:genetics / Q000378:metabolism; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport; D059748:Proteolysis / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000600:Amino Acids, Dicarboxylic; D003517:Cyclopentanes; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064800:Prolyl-Hydroxylase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D002738:Chloroquine; D064828:Prolyl Hydroxylases; D046988:Proteasome Endopeptidase Complex; C539933:pevonedistat; D010100:Oxygen; C040947:oxalylglycine
keywords: ENDOPLASMIC RETICULUM; GOLGI; HIF1a; HYPOXIA; LYSOSOME; MELANOMA