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Molecular and Cellular Biology, September 2002, p. 6122-6130, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6122-6130.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of {alpha}-Fetoprotein Expression by Nkx2.8

Yasuo Kajiyama, Jianmin Tian, and Joseph Locker*

Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461

Received 8 February 2002/ Returned for modification 6 May 2002/ Accepted 4 June 2002

The {alpha}-fetoprotein (AFP) gene is an important model of developmental gene silencing and neoplastic gene reactivation. Nkx2.8 is a divergent homeodomain factor originally cloned through its binding to the promoter-coupling element (PCE), a regulatory region upstream of the AFP promoter that mediates stimulation by distant enhancers. Nkx2.8 is the only developmentally regulated factor that has been associated with AFP gene expression. Fetoprotein transcription factor, an orphan nuclear receptor, has also been shown to bind the PCE but is not developmentally regulated. The binding specificities of both families of transcription factor were determined, and overlapping sites for each were defined in the PCE. After modification of nuclear extract and gel shift analysis procedures, Nkx2.8 was identified in six AFP-positive cell lines. Transient-transfection analysis did not show transcriptional stimulation by Nkx2.8 or other active NK2 factors, which only interfered with gene expression. However, two sets of analysis demonstrated the relationship of Nkx2.8 to AFP expression: chromatin immunoprecipitation demonstrated that Nkx2.8 bound to the active AFP promoter, and antisense inhibition of Nkx2.8 mRNA translation selectively reduced expression of both the endogenous human AFP gene and transfected reporters containing the rat AFP promoter.

* Corresponding author. Mailing address: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461-1975. Phone: (718) 430-3422. Fax: (718) 430-3483. E-mail: locker{at}aecom.yu.edu.

Molecular and Cellular Biology, September 2002, p. 6122-6130, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6122-6130.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tian, J., Mahmood, R., Hnasko, R., Locker, J. (2006). Loss of Nkx2.8 Deregulates Progenitor Cells in the Large Airways and Leads to Dysplasia. Cancer Res. 66: 10399-10407 [Abstract] [Full Text]  
  • Kajiyama, Y., Tian, J., Locker, J. (2006). Characterization of Distant Enhancers and Promoters in the Albumin-{alpha}-Fetoprotein Locus during Active and Silenced Expression. J. Biol. Chem. 281: 30122-30131 [Abstract] [Full Text]  


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