1 The Discovery of TGF-β: A Historical Perspective

Abstract

HISTORICAL CONTEXT In the early 1970s, Todaro and Huebner, studying the transforming activity of C-type RNA tumor viruses, proposed the viral oncogene hypothesis suggesting that “oncogenes” were an important component of the virogene of RNA tumor viruses whose expression was suppressed in “normal” cells and that treatment of cells with carcinogens, mutagens, or radiation could activate expression of this viral information by inactivating a repressor (Todaro and Huebner 1972). A few years later, Bishop and Varmus, also studying the effects of RNA tumor viruses on malignant transformation, made the Nobel Prize–winning breakthrough that neoplastic transformation of a cell by the avian sarcoma virus was mediated by a single viral gene ( src —the “oncogene”) (Levinson et al. 1978) and, most significantly, that the product of the src gene, now known to be a cellular signaling mediator of signals from the platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors, was a slightly modified analog of a normal cellular protein (Stehelin et al. 1976). A few years later, they showed that the transforming retroviral oncogene, v-src , arose by transduction of the cellular gene c-src (Swanstrom et al. 1983). Around the same time, based on results from a collaboration with the Nobel Laureate Stanley Cohen, Todaro suggested that murine and feline tumor viruses transform cells by inducing cells to secrete a molecule functionally related to EGF that acted on the same cells to effect their transformation (Todaro et al. 1976) (later termed autocrine secretion [Sporn and Todaro 1980]). Along similar lines,...