Protective Roles of NF-kB for Chromium (VI)-Induced Cytotoxicity Is Revealed by Expression of IkB Kinase-B Mutant

Details

• Personal Author:
  Bower J ; Castranova, Vincent ; Chen F ; Ding M ; Kung H ; Leonard, Stephanie ; Lu Y ; Rojanasakul Y ; Shi X ; Vallyathan V
• Description:
  To delineate the molecular mechanisms of NF-B-mediated regulation of chromium(VI)-induced cell death, the signaling pathway leading to the activation of NF-B was interrupted by stable transfection of a kinase-mutated form of IB kinase (IKK-KM). Here we demonstrate a novel role for the NF-B transcription factor in inhibiting chromium(VI)-induced cell death. Inhibition of NF-B by IKK-KM or IKK gene deficiency resulted in a spontaneous cleavage of Bcl-xl antiapoptotic protein due to the elevated caspase-3 activity. DNA microarray assay suggested a decreased expression of genes encoding antiapoptotic proteins, cIAP1 and cIAP2, in the cells overexpressing IKK-KM. Chromium(VI) treatment of these NF-B-inhibited cells induced necrotic-like cell death. Such chromium(VI)-induced cell killing could be partially inhibited by expression of exogenous cIAP1, an inhibitor of caspases, indicating that caspases along with others may be involved in chromium(VI)-induced cell death. These results suggest that NF-B is essential for inhibiting toxic metal-induced cytotoxicity. Such inhibition may involve up-regulation of the expression of anti-death proteins including cIAP1 that prevents spontaneous caspase activation and subsequent cleavage of Bcl-xl protein. [Description provided by NIOSH]
• Subjects:
  Carcinogens Chromium Cytotoxins Hazardous Substances Occupational Health Safety
• Keywords:
  Carcinogenesis Chromium-compounds Cytotoxicity Humans Toxic-effects
• ISSN:
  0021-9258
• Document Type:
  Text
• Funding:
  Interagency Agreement
• 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:
  277
• Issue:
  5
• NIOSHTIC Number:
  nn:20022295
• Citation:
  J Biol Chem 2002 Feb; 277(5):3342-3349
• Contact Point Address:
  PPRB of NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505
• Email:
  xshi@cdc.gov
• CAS Registry Number:
  Chromium (CAS RN 7440-47-3) ; Chromium(6+) (CAS RN 18540-29-9)
• Federal Fiscal Year:
  2002
• NORA Priority Area:
  Research Tools and Approaches: Cancer Research Methods
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Biological Chemistry
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:59445649a3fbb02272dbb5b43cb7518aabd30117f18689005357b18781f7c2899e8add78d270065d6c0683ef3d87464fddc6ecb61733a2d727fe496ad7d3c7f2
• Download URL:
  https://stacks.cdc.gov/view/cdc/199114/cdc_199114_DS1.pdf
• File Type:
  [PDF - 454.83 KB ]