PMID- 22415309
OWN - NLM
STAT- MEDLINE
DCOM- 20120820
LR  - 20211203
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 26
IP  - 6
DP  - 2012 Jun
TI  - Hypoxia induces IGFBP3 in esophageal squamous cancer cells through 
      HIF-1alpha-mediated mRNA transcription and continuous protein synthesis.
PG  - 2620-30
LID - 10.1096/fj.11-198598 [doi]
AB  - Insulin-like growth factor binding protein (IGFBP)-3 regulates cell proliferation 
      and apoptosis in esophageal squamous cell carcinoma (ESCC) cells. We have 
      investigated how the hypoxic tumor microenvironment in ESCC fosters the induction 
      of IGFBP3. RNA interference experiments revealed that hypoxia-inducible factor 
      (HIF)-1alpha, but not HIF-2alpha, regulates IGFBP3 mRNA induction. By chromatin 
      immunoprecipitation and transfection assays, HIF-1alpha was found to transactivate 
      IGFBP3 through a novel hypoxia responsive element (HRE) located at 57 kb upstream 
      from the transcription start site. Metabolic labeling experiments demonstrated 
      hypoxia-mediated inhibition of global protein synthesis. 7-Methyl GTP-cap binding 
      assays suggested that hypoxia suppresses cap-dependent translation. Experiments 
      using pharmacological inhibitors for mammalian target of rapamycin (mTOR) 
      suggested that a relatively weak mTOR activity may be sufficient for 
      cap-dependent translation of IGFBP3 under hypoxic conditions. Bicistronic RNA 
      reporter transfection assays did not validate the possibility of an internal 
      ribosome entry site as a potential mechanism for cap-independent translation for 
      IGFBP3 mRNA. Finally, IGFBP3 mRNA was found enriched to the polysomes. In 
      aggregate, our study establishes IGFBP3 as a direct HIF-1alpha target gene and that 
      polysome enrichment of IGFBP3 mRNA may permit continuous translation under 
      hypoxic conditions.
FAU - Natsuizaka, Mitsuteru
AU  - Natsuizaka M
AD  - Gastroenterology Division, Department of Medicine, University of Pennsylvania, 
      Philadelphia, Pennsylvania 19104-2144, USA.
FAU - Naganuma, Seiji
AU  - Naganuma S
FAU - Kagawa, Shingo
AU  - Kagawa S
FAU - Ohashi, Shinya
AU  - Ohashi S
FAU - Ahmadi, Azal
AU  - Ahmadi A
FAU - Subramanian, Harry
AU  - Subramanian H
FAU - Chang, Sanders
AU  - Chang S
FAU - Nakagawa, Kei J
AU  - Nakagawa KJ
FAU - Ji, Xinjun
AU  - Ji X
FAU - Liebhaber, Stephen A
AU  - Liebhaber SA
FAU - Klein-Szanto, Andres J
AU  - Klein-Szanto AJ
FAU - Nakagawa, Hiroshi
AU  - Nakagawa H
LA  - eng
GR  - R01 DK077005/DK/NIDDK NIH HHS/United States
GR  - P30 DK050306/DK/NIDDK NIH HHS/United States
GR  - R37-HL65449/HL/NHLBI NIH HHS/United States
GR  - R01DK077005/DK/NIDDK NIH HHS/United States
GR  - P01 CA098101/CA/NCI NIH HHS/United States
GR  - P30 CA016520/CA/NCI NIH HHS/United States
GR  - R37 HL065449/HL/NHLBI NIH HHS/United States
GR  - P01CA098101/CA/NCI NIH HHS/United States
GR  - P30-DK050306/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120313
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 3)
RN  - 0 (RNA Cap Analogs)
RN  - 0 (RNA Caps)
RN  - 0 (RNA, Messenger)
RN  - 45LQ9B0V54 (7-methylguanosine triphosphate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Carcinoma, Squamous Cell/metabolism
MH  - Cell Line, Tumor
MH  - Esophageal Neoplasms/metabolism
MH  - Humans
MH  - Hypoxia/*physiopathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Insulin-Like Growth Factor Binding Protein 3/*biosynthesis/metabolism
MH  - Mice
MH  - Neoplasm Transplantation
MH  - Polyribosomes/metabolism
MH  - *Protein Biosynthesis
MH  - RNA Cap Analogs/metabolism
MH  - RNA Caps/metabolism
MH  - RNA, Messenger/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transcription, Genetic
MH  - Transplantation, Heterologous
PMC - PMC3360153
EDAT- 2012/03/15 06:00
MHDA- 2012/08/21 06:00
PMCR- 2013/06/01
CRDT- 2012/03/15 06:00
PHST- 2012/03/15 06:00 [entrez]
PHST- 2012/03/15 06:00 [pubmed]
PHST- 2012/08/21 06:00 [medline]
PHST- 2013/06/01 00:00 [pmc-release]
AID - fj.11-198598 [pii]
AID - 11-198598 [pii]
AID - 10.1096/fj.11-198598 [doi]
PST - ppublish
SO  - FASEB J. 2012 Jun;26(6):2620-30. doi: 10.1096/fj.11-198598. Epub 2012 Mar 13.