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Induction of Activating Transcription Factor 1 by Nickel and Its Role as a Negative Regulator of Thrombospondin I Gene Expression¹

Departments of Environmental Medicine [K. S., S. W., M. C.] and Pharmacology [M. C.] and The Kaplan Cancer Center [M. C.], New York University Medical Center, New York, New York 10016

Thrombospondin I (TSP I) is an extracellular matrix glycoprotein that influences cell adhesion, motility, and growth. On the basis of its effects on endothelial cell proliferation, TSP I has attracted interest as a potential regulator of solid tumor growth through modulation of tumor blood supply. The regulation of TSP I expression is of critical importance for designing new approaches in tumor therapy. Recently, we have shown that TSP I expression is lost in nickel-transformed cells. In this paper, we identified an activating transcription factor (ATF)/cAMP-responsive element-binding protein binding site as a negative regulatory site in the 5'-flanking sequence of mouse TSP I promoter. We identified ATF-1 as a major component of the ATF/cAMP-responsive element-binding protein binding complex. This M_r 35,000 nuclear ATF-1 protein was shown to be present in higher amounts in nickel-transformed 3T3 cells that do not express TSP I. Acute treatment of 3T3 cells with NiCl₂ resulted in the induction of this transcription factor, and this induction was correlated temporally with the suppression of TSP I expression in the same cells. These results show that nickel exposure causes accumulation of the ATF-1 transcription factor, which is responsible for the down-regulation of transcription of TSP I, and possibly other tumor suppressor genes during nickel-induced cellular transformation.

¹ This work was supported by NIH Grants ES04895, ES05515, ES00260, and CA16037.

² To whom requests for reprints should be addressed, at Department of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016. Phone: (914) 351-3378; Fax: (914) 351-2118; E-mail: salnikow@charlotte.med.nyu.edu.

³ Present address: Columbia University Medical School, New York, NY.

Received 5/13/97. Accepted 9/19/97.

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