Incorporation of an Internal Ribosome Entry Site-Dependent Mechanism in Arsenic-Induced GADD45alpha Expression

Details

• Personal Author:
  Bhatia D ; Castranova, Vincent ; Chang Q ; Chen F ; Meighan T ; Shi X ; Zhang Y
• Description:
  We have previously shown that trivalent arsenic (arsenite, As3+) is able to induce GADD45alpha expression in human bronchial epithelial cells through activation of c-Jun NH2-terminal kinase and nucleolin-dependent mRNA stabilization. In the present report, we show that As3+ is capable of inducing translation of the GADD45alpha protein through a cap-independent, or rather, an internal ribosome entry site (IRES)-dependent mechanism. In growth-arrested cells, As3+ elevated the GADD45alpha protein level in a dose- and time-dependent manner which did not correlate with the GADD45 mRNA expression. Pretreatment of the cells with rapamycin, an inhibitor for the cap-dependent translation machinery through the suppression of mTOR and p70S6 kinase, failed to affect the induction of the GADD45alpha protein induced by As3+. Sequence analysis revealed a potential IRES element in the 5'-untranslated region of the GADD45alpha mRNA. This IRES element in the 5'-untranslated region of the GADD45alpha mRNA is functional in mediating As3+-induced translation of the GADD45alpha protein in a dicistronic reporter gene activity assay. Immunoprecipitation and proteomic studies suggest that As3+ impairs the assembly of the cap-dependent initiating complex for general protein translation but increases the association of human elongation factor 2 and human heterogeneous nuclear ribonucleoprotin with this complex. Thus, these results suggest that in growth-arrested cells, As3+ is still capable of inducing GADD45alpha expression through an IRES-dependent translational regulation. [Description provided by NIOSH]
• Subjects:
  Arsenic Chemistry Hypersensitivity Inorganic Chemicals Irritants Lung Occupational Health Poisoning Respiratory System Respiratory Tract Diseases Safety

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• Keywords:
  Arsenic-compounds Arsenic-poisoning Breathing Chemical-hypersensitivity Chemical-properties Chemical-synthesis Lung-cells Lung-irritants Respiratory-irritants Respiratory-system-disorders
• ISSN:
  0008-5472
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  67
• Issue:
  13
• NIOSHTIC Number:
  nn:20032492
• Citation:
  Cancer Res 2007 Jul; 67(13):6146-6154
• Contact Point Address:
  Fei Chen, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505
• Email:
  LFD3@cdc.gov
• CAS Registry Number:
  Arsenic (CAS RN 7440-38-2)
• Federal Fiscal Year:
  2007
• NORA Priority Area:
  Manufacturing ; Mining
• Peer Reviewed:
  True
• Source Full Name:
  Cancer Research
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d58e81e04ebe62c096617f34e9d0948f8b3fa866c321b2d36788644c80e1c64a2ed37af1699b40edad3b6f2f01a9ffb683e6b8d74ee0a391e9f94619f421418c
• Download URL:
  https://stacks.cdc.gov/view/cdc/186435/cdc_186435_DS1.pdf
• File Type:
  [PDF - 901.36 KB ]