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Molecular and Cellular Biology, June 1999, p. 4219-4230, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Platelet-Derived Growth Factor-Stimulated Expression of the MCP-1 Immediate-Early Gene Involves an Inhibitory Multiprotein Complex

Padma Sridhar,1 Yu Liu,1 Lisa D. Chin,1 Charlene E. Borja,1 Mana Mann,1 Hal A. Skopicki,2 and Rolf R. Freter1,*

Division of Medical Oncology1 and Division of Circulatory Physiology,2 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032

Received 10 December 1998/Returned for modification 5 February 1999/Accepted 24 March 1999

We have demonstrated previously that the seven-nucleotide (nt) motif TTTTGTA (the heptamer) that is present within the proximal 3' untranslated sequences of numerous immediate-early genes is essential for platelet-derived growth factor (PDGF)-stimulated induction of the MCP-1 immediate-early gene. On this basis, the heptamer was suggested to be a conserved regulatory element involved in immediate-early gene expression, although its mechanism of action was unknown. Herein, we demonstrate that the heptamer functions to remove an inhibition of PDGF induction of MCP-1 maintained by two independently acting inhibitory elements present in the MCP-1 5' flanking sequences (designated I* elements). PDGF treatment relieves the I*-mediated inhibition of MCP-1 expression only if the heptamer is also present. One inhibitory element is contained within a 59-nt portion of MCP-1 5' flanking sequences and functions in an orientation-independent and heptamer-regulated manner. Significantly, proteins binding to two DNA sequences contribute to the formation of a single multiprotein complex on the 59-nt I* element. The I*-binding complex contains Sp3, an Sp1-like protein, and a novel DNA-binding protein. Moreover, the complex does not form on two 59-nt sequences containing mutations that reverse the inhibition of PDGF induction maintained by the wild-type I* element. We propose to call the multiprotein I*-binding complex a repressosome and suggest that it acts to repress PDGF-stimulated transcription of MCP-1 in the absence of the heptamer TTTTGTA.

* Corresponding author. Mailing address: Columbia University, P+S Bldg., Room 10-432, 630 West 168th St., New York, NY 10032. Phone: (212) 305-3461. Fax: (212) 305-1912. E-mail: freter{at}cuccfa.ccc.columbia.edu.

Molecular and Cellular Biology, June 1999, p. 4219-4230, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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