Small GTPases and cell cycle regulation.

Introduction The Ras family of small GTPases was originally discovered as viral oncogenes ; subsequent studies demonstrated that the cellular proto-oncogenes are mutated in a high proportion of human tumours such as colorectal and pancreatic cancer [l]. Oncogenic mutations create forms of the Ras proteins that are constitutively active because they are locked in the active GTP-bound state [2]. Since the discovery of Ras oncogenes, a central issue in cancer research has been to understand the function of these proteins. The expression of oncogenic Ras proteins in established cell lines liberates the cells from the requirement for growth factors for proliferation [3] ; microinjection of recombinant Ras proteins into quiescent cells drives the cells into DNA synthesis [4,5]. These experiments indicate that oncogenic Ras proteins alter cell cycle regulation. Furthermore, classic experiments performed by Stacey and co-workers, with the use of microinjection of antibody to neutralize the function of normal Ras proteins in cells, showed that Ras is required for growth factors to stimulate cell proliferation [6 ] . The localization of Ras proteins to the inner surface of the plasma membrane suggests that they are involved in early steps of growth factor signalling mechanisms. The argument that Ras protein function was required for growth factors to stimulate cell proliferation was strengthened further by the demonstration that the treatment of quiescent cells with growth factors leads to the normal Ras proteins being converted into the active GTPbound state [7,8]. Thus Ras proteins act as a molecular switch to transduce signals from growth