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Molecular and Cellular Biology, August 2000, p. 5490-5502, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

HMG-I/Y, a New c-Myc Target Gene and Potential Oncogene

Lisa J. Wood,1,2 Mita Mukherjee,1,2 Christine E. Dolde,1,2 Yi Xu,1,2 Joseph F. Maher,3,dagger Tracie E. Bunton,4,Dagger John B. Williams,3 and Linda M. S. Resar1,2,3,5,*

Hematology Division1 and Departments of Pediatrics,2 Molecular Biology and Genetics,3 Comparative Medicine,4 and Oncology,5 The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Received 11 August 1999/Returned for modification 18 October 1999/Accepted 15 May 2000

The HMG-I/Y gene encodes the HMG-I and HMG-Y proteins, which function as architectural chromatin binding proteins important in the transcriptional regulation of several genes. Although increased expression of the HMG-I/Y proteins is associated with cellular proliferation, neoplastic transformation, and several human cancers, the role of these proteins in the pathogenesis of malignancy remains unclear. To better understand the role of these proteins in cell growth and transformation, we have been studying the regulation and function of HMG-I/Y. The HMG-I/Y promoter was cloned, sequenced, and subjected to mutagenesis analysis. A c-Myc-Max consensus DNA binding site was identified as an element important in the serum stimulation of HMG-I/Y. The oncoprotein c-Myc and its protein partner Max bind to this site in vitro and activate transcription in transfection experiments. HMG-I/Y expression is stimulated by c-Myc in a Myc-estradiol receptor cell line in the presence of the protein synthesis inhibitor cycloheximide, indicating that HMG-I/Y is a direct c-Myc target gene. HMG-I/Y induction is decreased in Myc-deficient fibroblasts. HMG-I/Y protein expression is also increased in Burkitt's lymphoma cell lines, which are known to have increased c-Myc protein. Like Myc, increased expression of HMG-I protein leads to the neoplastic transformation of both Rat 1a fibroblasts and CB33 cells. In addition, Rat 1a cells overexpressing HMG-I protein form tumors in nude mice. Decreasing HMG-I/Y proteins using an antisense construct abrogates transformation in Burkitt's lymphoma cells. These findings indicate that HMG-I/Y is a c-Myc target gene involved in neoplastic transformation and a member of a new class of potential oncogenes.

* Corresponding author. Mailing address: The Johns Hopkins University School of Medicine, Division of Pediatric Hematology, The Ross Research Bldg., Room 1125, 720 Rutland Ave., Baltimore, MD 21205. Phone: (410) 955-6132. Fax: (410) 955-8208. E-mail: lmsresar{at}welch.jhu.edu.

dagger Present address: University of Mississippi Medical Center/G. V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS 39216.

Dagger Present address: DuPont Pharmaceutical Company, Stine-Haskell Research Center, Newark, DE 19714-0300.

Molecular and Cellular Biology, August 2000, p. 5490-5502, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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