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Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis
Authors: Garayoa, M. (Mercedes)
Martinez, A. (Alfredo)
Lee, S. (Sunmin)
Pio, R. (Rubén)
An, W.G. (Won G.)
Neckers, L. (Len)
Trepel, J. (Jane)
Montuenga, L.M. (Luis M.)
Ryan, H. (Heather)
Johnson, R. (Randall)
Gassmann, M. (Max)
Cuttitta, F. (Frank)
Keywords: Cell Hypoxia
DNA-Binding Proteins/pharmacology
Gene Expression Regulation, Neoplastic/drug effect
Neoplasms/metabolism
Nuclear Proteins/pharmacology
Peptides/genetics
Transcription Factors
Issue Date: 2000
Publisher: Endocrine Society
Publisher version: http://mend.endojournals.org/content/14/6/848
ISSN: 1944-9917
Citation: Garayoa M, Martinez A, Lee S, Pio R, An WG, Neckers L, et al. Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis. Mol Endocrinol 2000 Jun;14(6):848-862.
Abstract
Little is known about the molecular mechanisms that control adrenomedullin (AM) production in human cancers. We demonstrate here that the expression of AM mRNA in a variety of human tumor cell lines is highly induced in a time-dependent manner by reduced oxygen tension (1% O2) or exposure to hypoxia mimetics such as desferrioxamine mesylate (DFX) or CoCl2. This AM expression seems to be under hypoxia-inducible factor-1 (HIF-1) transcriptional regulation, since HIF-1alpha and HIF-1beta knockout mouse cell lines had an ablated or greatly reduced hypoxia AM mRNA induction. Similarly, inhibition or enhancement of HIF-1 activity in human tumor cells showed an analogous modulation of AM mRNA. Under hypoxic conditions, immunohistochemical analysis of tumor cell lines revealed elevated levels of AM and HIF-1alpha as compared with normoxia, and we also found an increase of immunoreactive AM in the conditioned medium of tumor cells analyzed by RIA. AM mRNA stabilization was shown to be partially responsible for the hypoxic up-regulated expression of AM. In addition, we have identified several putative hypoxia response elements (HREs) in the human AM gene, and reporter studies with selected HREs were capable of enhancing luciferase expression after exposure to DFX. Furthermore, transient coexpression of HIF-1alpha resulted in an augmented transactivation of the reporter gene after DFX treatment. Given that most solid human tumors have focal hypoxic areas and that AM functions as a mitogen, angiogenic factor, and apoptosis-survival factor, our findings implicate the HIF-1/AM link as a possible promotion mechanism of carcinogenesis.
Permanent link: http://hdl.handle.net/10171/20173
Appears in Collections:DA - Ciencias - HAP - Artículos de revista
DA - CIMA - Oncología - Biomarcadores - Artículos de Revista

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