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Volume 272, Number 8, Issue of February 21, 1997 pp. 5313-5319
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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2-Aminopurine Unravels a Role for pRB in the Regulation of Gene Expression by Transforming Growth Factor

(Received for publication, July 23, 1996, and in revised form, November 4, 1996)

Giuseppe Giannini , Lucia Di Marcotullio , Francesca Zazzeroni , Edoardo Alesse , Massimo Zani ^¶ , Anne T'Ang , Vincenzo Sorrentino ^**§§ , Isabella Screpanti ^¶ , Luigi Frati ^¶¶¶ and Alberto Gulino

From the  Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy, the ^¶ Department of Experimental Medicine and Pathology, University "La Sapienza," 00161 Rome, Italy, the ^¶¶ Neurological Mediterranean Institute, Neuromed, Pozzilli, Italy, the  Department of Pediatrics and Microbiology, School of Medicine, Children's Hospital of Los Angeles, Los Angeles, California 90027, ^** Dibit, San Raffaele Scientific Institute, 20132 Milano, Italy, and the ^§§ Institute of Histology, School of Medicine, University of Siena, 53100 Siena, Italy

Transforming growth factor type  (TGF) is a pleiotropic factor that regulates different cellular activities including cell growth, differentiation, and extracellular matrix deposition. All the known effects of TGF appear to be mediated by its interaction with cell surface receptors that possess a serine/threonine kinase activity. However, the intracellular signals that follow receptor activation and lead to the different cellular responses to TGF are still largely unknown. On the basis of the different sensitivity to the protein kinase inhibitor 2-aminopurine and the phosphatase inhibitor okadaic acid, we identified two distinct pathways through which TGF activates a genomic response. Consistently, 2-aminopurine prevented and okadaic acid potentiated the induction of JE by TGF. The induction of PAI-1 and junB was instead potentiated by 2-aminopurine, after a transient inhibition and was unaffected by okadaic acid. The superinducing effect of 2-aminopurine required the presence of a functional RB protein since it was abolished in SV40 large T antigen-transfected cells, absent in the BT549 and Saos-2 RB-defective cell lines, and restored in BT549 and Saos-2 cells after reintroduction of pRB. The effects of 2-aminopurine on the TGF inducible junB expression occur in all the cell lines examined suggesting that junB, and possibly other genes, can be regulated by TGF through a distinct pRB-dependent pathway.

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