Translational and transcriptional control of Sp1 against ischaemia through a hydrogen peroxide-activated internal ribosomal entry site pathway

Shiu Hwa Yeh, Wen Bin Yang, Po Wu Gean, Chung Yi Hsu, Joseph T. Tseng, Tsung Ping Su, Wen Chang Chang, Jan Jong Hung

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The exact mechanism underlying increases in Sp1 and the physiological consequences thereafter remains unknown. In rat primary cortical neurons, oxygen-glucose deprivation (OGD) causes an increase in H2O2 as well as Sp1 in early ischaemia but apparently does not change mRNA level or Sp1 stability. We hereby identified a longer 5′-UTR in Sp1 mRNA that contains an internal ribosome entry site (IRES) that regulates rapid and efficient translation of existing mRNAs. By using polysomal fragmentation and bicistronic luciferase assays, we found that H2O2 activates IRES-dependent translation. Thus, H2O2 or tempol, a superoxide dismutase-mimetic, increases Sp1 levels in OGD-treated neurons. Further, early-expressed Sp1 binds to Sp1 promoter to cause a late rise in Sp1 in a feed-forward manner. Short hairpin RNA against Sp1 exacerbates OGD-induced apoptosis in primary neurons. While Sp1 levels increase in the cortex in a rat model of stroke, inhibition of Sp1 binding leads to enhanced apoptosis and cortical injury. These results demonstrate that neurons can use H2O2 as a signalling molecule to quickly induce Sp1 translation through an IRES-dependent translation pathway that, in cooperation with a late rise in Sp1 via feed-forward transcriptional activation, protects neurons against ischaemic damage.

Original languageEnglish
Pages (from-to)5412-5423
Number of pages12
JournalNucleic Acids Research
Volume39
Issue number13
DOIs
Publication statusPublished - Jul 2011
Externally publishedYes

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Hydrogen Peroxide
Ischemia
Neurons
Oxygen
Glucose
Apoptosis
Messenger RNA
5' Untranslated Regions
Protein Biosynthesis
Luciferases
Small Interfering RNA
Transcriptional Activation
Superoxide Dismutase
Stroke
Wounds and Injuries
Internal Ribosome Entry Sites

ASJC Scopus subject areas

  • Genetics

Cite this

Translational and transcriptional control of Sp1 against ischaemia through a hydrogen peroxide-activated internal ribosomal entry site pathway. / Yeh, Shiu Hwa; Yang, Wen Bin; Gean, Po Wu; Hsu, Chung Yi; Tseng, Joseph T.; Su, Tsung Ping; Chang, Wen Chang; Hung, Jan Jong.

In: Nucleic Acids Research, Vol. 39, No. 13, 07.2011, p. 5412-5423.

Research output: Contribution to journalArticle

Yeh, Shiu Hwa ; Yang, Wen Bin ; Gean, Po Wu ; Hsu, Chung Yi ; Tseng, Joseph T. ; Su, Tsung Ping ; Chang, Wen Chang ; Hung, Jan Jong. / Translational and transcriptional control of Sp1 against ischaemia through a hydrogen peroxide-activated internal ribosomal entry site pathway. In: Nucleic Acids Research. 2011 ; Vol. 39, No. 13. pp. 5412-5423.
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