Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia

HIF-1-independent mechanisms

Zheng Dong, Manjeri A. Venkatachalam, Jinzhao Wang, Yogendra Patel, Pothana Saikumar, Gregg L. Semenza, Thomas Force, Junichiro Nishiyama

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Hypoxia is a key determinant of tissue pathology during tumor development and organ ischemia. However, little is known regarding hypoxic regulation of genes that are directly involved in cell death or death resistance. Here we report the striking induction by severe hypoxia of the anti-apoptotic protein IAP-2. Hypoxic cells with IAP-2 up-regulation became resistant to apoptosis. IAP-2 was induced by hypoxia per se rather than by the secondary effects of hypoxia, including ATP depletion and cell injury. The inductive response did not relate to alterations of cellular redox status or arrest of mitochondrial respiration. On the other hand, IAP-2 induction was attenuated by actinomycin D, suggesting a role for gene transcription. In vitro nuclear run-on assays demonstrated specific increases in IAP-2 transcriptional activity after hypoxia exposure. HIF-1, the primary transcription factor that is responsible for multiple gene activation under hypoxia, does not have a role in IAP-2 expression. HIF-1 and IAP-2 were induced by different degrees of hypoxia; severe hypoxia or anoxia was required for IAP-2 induction. Moreover, cobalt chloride and desferrioxamine activated HIF-1 but not IAP-2. Finally, IAP-2 was induced by severe hypoxia in mouse embryonic stem cells that were deficient of HIF-1. Thus, this study not only provides the first demonstration of hypoxic regulation of an anti-apoptotic gene but also suggests the participation of novel hypoxia-responsive transcription mechanisms.

Original languageEnglish (US)
Pages (from-to)18702-18709
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number22
DOIs
StatePublished - Jun 1 2001

Fingerprint

Inhibitor of Apoptosis Proteins
Up-Regulation
Genes
Apoptosis
Transcription
Proteins
Apoptosis Regulatory Proteins
Deferoxamine
Dactinomycin
Pathology
Cell death
Stem cells
Tumors
Assays
Transcription Factors
Demonstrations
Adenosine Triphosphate
Chemical activation
Cells
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Dong, Z., Venkatachalam, M. A., Wang, J., Patel, Y., Saikumar, P., Semenza, G. L., ... Nishiyama, J. (2001). Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia: HIF-1-independent mechanisms. Journal of Biological Chemistry, 276(22), 18702-18709. https://doi.org/10.1074/jbc.M011774200

Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia : HIF-1-independent mechanisms. / Dong, Zheng; Venkatachalam, Manjeri A.; Wang, Jinzhao; Patel, Yogendra; Saikumar, Pothana; Semenza, Gregg L.; Force, Thomas; Nishiyama, Junichiro.

In: Journal of Biological Chemistry, Vol. 276, No. 22, 01.06.2001, p. 18702-18709.

Research output: Contribution to journalArticle

Dong, Z, Venkatachalam, MA, Wang, J, Patel, Y, Saikumar, P, Semenza, GL, Force, T & Nishiyama, J 2001, 'Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia: HIF-1-independent mechanisms', Journal of Biological Chemistry, vol. 276, no. 22, pp. 18702-18709. https://doi.org/10.1074/jbc.M011774200
Dong, Zheng ; Venkatachalam, Manjeri A. ; Wang, Jinzhao ; Patel, Yogendra ; Saikumar, Pothana ; Semenza, Gregg L. ; Force, Thomas ; Nishiyama, Junichiro. / Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia : HIF-1-independent mechanisms. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 22. pp. 18702-18709.
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