Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2002 Oct;110(Suppl 5):783–788. doi: 10.1289/ehp.02110s5783

Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells.

Hakan Cangul 1, Konstantin Salnikow 1, Herman Yee 1, David Zagzag 1, Therese Commes 1, Max Costa 1
PMCID: PMC1241245  PMID: 12429530

Abstract

Cap43 is a protein whose RNA is induced under conditions of severe hypoxia or prolonged elevations of intracellular calcium. Additionally, Ni and Co also induce Cap43 because they produce a state of hypoxia in cells. Cap43 protein is expressed at low levels in normal tissues; however, in a variety of cancers, including lung, brain, melanoma, liver, prostate, breast, and renal cancers, Cap43 protein is overexpressed in cancer cells. The low level of expression of Cap43 in some normal tissues compared with their cancerous counterparts, combined with the high stability of Cap43 protein and mRNA, makes the Cap43 gene a new, important cancer marker. We hypothesize that the mechanism of Cap43 overexpression in cancer cells involves a state of hypoxia characteristic of cancer cells where the Cap43 protein becomes a signature for this hypoxic state.

Full Text

The Full Text of this article is available as a PDF (624.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blagosklonny M. V. Loss of function and p53 protein stabilization. Oncogene. 1997 Oct 16;15(16):1889–1893. doi: 10.1038/sj.onc.1201374. [DOI] [PubMed] [Google Scholar]
  2. Fatatis A., Miller R. J. Sphingosine and sphingosine 1-phosphate differentially modulate platelet-derived growth factor-BB-induced Ca2+ signaling in transformed oligodendrocytes. J Biol Chem. 1996 Jan 5;271(1):295–301. doi: 10.1074/jbc.271.1.295. [DOI] [PubMed] [Google Scholar]
  3. Gardner L. B., Li Q., Park M. S., Flanagan W. M., Semenza G. L., Dang C. V. Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem. 2000 Dec 8;276(11):7919–7926. doi: 10.1074/jbc.M010189200. [DOI] [PubMed] [Google Scholar]
  4. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  5. Kurdistani S. K., Arizti P., Reimer C. L., Sugrue M. M., Aaronson S. A., Lee S. W. Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res. 1998 Oct 1;58(19):4439–4444. [PubMed] [Google Scholar]
  6. Madan A., Curtin P. T. A 24-base-pair sequence 3' to the human erythropoietin gene contains a hypoxia-responsive transcriptional enhancer. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3928–3932. doi: 10.1073/pnas.90.9.3928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Murray G. I., Taylor M. C., McFadyen M. C., McKay J. A., Greenlee W. F., Burke M. D., Melvin W. T. Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res. 1997 Jul 15;57(14):3026–3031. [PubMed] [Google Scholar]
  8. Muskhelishvili L., Thompson P. A., Kusewitt D. F., Wang C., Kadlubar F. F. In situ hybridization and immunohistochemical analysis of cytochrome P450 1B1 expression in human normal tissues. J Histochem Cytochem. 2001 Feb;49(2):229–236. doi: 10.1177/002215540104900210. [DOI] [PubMed] [Google Scholar]
  9. Ryan H. E., Lo J., Johnson R. S. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998 Jun 1;17(11):3005–3015. doi: 10.1093/emboj/17.11.3005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Salnikow K., An W. G., Melillo G., Blagosklonny M. V., Costa M. Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. Carcinogenesis. 1999 Sep;20(9):1819–1823. doi: 10.1093/carcin/20.9.1819. [DOI] [PubMed] [Google Scholar]
  11. Salnikow K., Blagosklonny M. V., Ryan H., Johnson R., Costa M. Carcinogenic nickel induces genes involved with hypoxic stress. Cancer Res. 2000 Jan 1;60(1):38–41. [PubMed] [Google Scholar]
  12. Salnikow K., Costa M., Figg W. D., Blagosklonny M. V. Hyperinducibility of hypoxia-responsive genes without p53/p21-dependent checkpoint in aggressive prostate cancer. Cancer Res. 2000 Oct 15;60(20):5630–5634. [PubMed] [Google Scholar]
  13. Salnikow K., Kluz T., Costa M. Role of Ca(2+) in the regulation of nickel-inducible Cap43 gene expression. Toxicol Appl Pharmacol. 1999 Oct 15;160(2):127–132. doi: 10.1006/taap.1999.8759. [DOI] [PubMed] [Google Scholar]
  14. Semenza G. L., Agani F., Booth G., Forsythe J., Iyer N., Jiang B. H., Leung S., Roe R., Wiener C., Yu A. Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int. 1997 Feb;51(2):553–555. doi: 10.1038/ki.1997.77. [DOI] [PubMed] [Google Scholar]
  15. Zhou D., Salnikow K., Costa M. Cap43, a novel gene specifically induced by Ni2+ compounds. Cancer Res. 1998 May 15;58(10):2182–2189. [PubMed] [Google Scholar]
  16. van Belzen N., Dinjens W. N., Diesveld M. P., Groen N. A., van der Made A. C., Nozawa Y., Vlietstra R., Trapman J., Bosman F. T. A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms. Lab Invest. 1997 Jul;77(1):85–92. [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES