PMID- 10847587
OWN - NLM
STAT- MEDLINE
DCOM- 20001003
LR  - 20131121
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 14
IP  - 6
DP  - 2000 Jun
TI  - Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in 
      human tumor cell lines during oxygen deprivation: a possible promotion mechanism 
      of carcinogenesis.
PG  - 848-62
AB  - 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.
FAU - Garayoa, M
AU  - Garayoa M
AD  - Department of Cell and Cancer Biology, National Cancer Institute, National 
      Institutes of Health Bethesda, Maryland 20892, USA. garayoam@bprb.nci.nih.gov
FAU - Martinez, A
AU  - Martinez A
FAU - Lee, S
AU  - Lee S
FAU - Pio, R
AU  - Pio R
FAU - An, W G
AU  - An WG
FAU - Neckers, L
AU  - Neckers L
FAU - Trepel, J
AU  - Trepel J
FAU - Montuenga, L M
AU  - Montuenga LM
FAU - Ryan, H
AU  - Ryan H
FAU - Johnson, R
AU  - Johnson R
FAU - Gassmann, M
AU  - Gassmann M
FAU - Cuttitta, F
AU  - Cuttitta F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Peptides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 148498-78-6 (Adrenomedullin)
RN  - 9007-49-2 (DNA)
RN  - EC 1.13.12.- (Luciferases)
RN  - J06Y7MXW4D (Deferoxamine)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Adrenomedullin
MH  - *Cell Hypoxia
MH  - Culture Media, Conditioned
MH  - DNA/chemistry/metabolism
MH  - DNA-Binding Proteins/analysis/*pharmacology
MH  - Deferoxamine/pharmacology
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Immunohistochemistry
MH  - Luciferases/genetics
MH  - Neoplasms/*metabolism
MH  - Nuclear Proteins/analysis/*pharmacology
MH  - Oxygen/administration & dosage
MH  - Peptides/analysis/*genetics/metabolism
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/biosynthesis/metabolism
MH  - Response Elements
MH  - *Transcription Factors
MH  - Tumor Cells, Cultured
EDAT- 2000/06/10 09:00
MHDA- 2000/10/07 11:01
CRDT- 2000/06/10 09:00
PHST- 2000/06/10 09:00 [pubmed]
PHST- 2000/10/07 11:01 [medline]
PHST- 2000/06/10 09:00 [entrez]
AID - 10.1210/mend.14.6.0473 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2000 Jun;14(6):848-62. doi: 10.1210/mend.14.6.0473.