The Tmp Gene, Encoding a Membrane Protein, Is a c-Myc Target with a Tumorigenic Activity

Abstract

The c-Myc oncoprotein induces cell proliferation and transformation through its activity as a transcription factor. Uncovering the genes regulated by c-Myc is an essential step for understanding these processes. We recently isolated the tumor-associated membrane protein gene, Tmp, from a c-myc-induced mouse brain tumor. Here we show that Tmp is specifically highly expressed in mammary tumors and T-cell lymphomas which develop in c-myc transgenic mice, suggesting that Tmpexpression is a general characteristic of c-Myc-induced tumors. In addition, Tmp expression is induced upon serum stimulation of fibroblasts as shown in a time course closely correlated with c-myc expression. We have isolated the Tmppromoter region and identified a putative c-Myc binding element, CACGTG, located in the first intron of the gene. We show here that constructs containing the Tmp regulatory region fused to a reporter gene are activated by c-Myc through this CACGTG element and that the c-Myc–Max protein complex can bind to this element. Moreover, an inducible form of c-Myc, the MycER fusion protein, can activate the endogenous Tmp gene. We also show that Tmp-overexpressing fibroblasts induce rapidly growing tumors when injected into nude mice, suggesting that Tmp may possess a tumorigenic activity. Thus, TMP, a member of a novel family of membrane glycoproteins with a suggested role in cellular contact, is a c-Myc target and is possibly involved in c-Myc-induced transformation.

ACKNOWLEDGMENTS

This research was supported by grant 3811a from The Council for Tobacco Research, by grant 93-00017 from The U.-S.-Israel Binational Science Foundation, Jerusalem, Israel, and by a grant from The Israel Science Foundation, funded by The Israel Academy of Sciences and Humanities.

We thank the following investigators: Linda Z. Penn for the Rat1-MycER cells, Ari Elson and Ian Krane for the RNA blots of tumor cell lines from transgenic mice, Thanos Halazonetis for the MBP-Myc and MBP-Max proteins, and Chaim Kahana for advice with the experiments. We thank Ayellet Falcovitz and Irit Marbach for assistance with the experiments. We thank Shoshana Klein, Amir Eden, and Yuval Dor for critical reading of the manuscript.