Cell Growth & Differentiation, Vol 6, Issue 10 1225-1234, Copyright © 1995 by American Association of Cancer Research

ARTICLES

Mitogenesis by v-Src: fluctuations throughout G1 of classical immediate early AP-1 and mitogen-activated protein kinase responses that parallel the need for the oncoprotein

AW Wyke, MC Frame, DA Gillespie, A Chudleigh and JA Wyke
Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsden, Glasgow, Scotland.

Activation of the tyrosine kinase of a temperature-sensitive mutant v-Src oncoprotein in quiescent Rat-1 cells leads to passage through the cell cycle. Temperature shift experiments show that v-Src is needed to leave G0, to pass a relatively stable G1 "pause" point, and to pass a later G1 point committing cells to S phase. Classic immediate early responses that activate both AP-1 DNA binding and mitogen-activated protein (MAP) kinase are induced at G0 exit, but unexpectedly they rise again in mid-G1 and before the onset of S phase, fluctuations that parallel the need for v-Src. An estrogen-inducible mutant c-Raf-1 renders these cells susceptible to mitogenic stimulation by beta-estradiol, without v-Src activity, but greatly inhibits the ability of v-Src to induce DNA synthesis and MAP kinase, probably because v-Src physically associates with inactive c-Raf-1 at permissive but not restrictive temperature. This implicates c-Raf-1 association with enzymically active v-Src and consequent activation of the MAP kinase pathway in v-Src mitogenesis. Furthermore, temperature shift experiments indicate that the mid-G1 peak of MAP kinase activity is associated with cells reaching the G1 pause point, while the pre-S phase peak is needed for DNA synthesis. In contrast, cell transformation by v-Src does not require enhanced MAP kinase activity at any stage of the cell cycle.

This article has been cited by other articles:

				V. Fincham, A Chudleigh, and M. Frame Regulation of p190 Rho-GAP by v-Src is linked to cytoskeletal disruption during transformation J. Cell Sci., January 3, 1999; 112(6): 947 - 956. [Abstract] [PDF]

				N. O. Carragher, V. J. Fincham, D. Riley, and M. C. Frame Cleavage of Focal Adhesion Kinase by Different Proteases during Src-regulated Transformation and Apoptosis. DISTINCT ROLES FOR CALPAIN AND CASPASES J. Biol. Chem., February 2, 2001; 276(6): 4270 - 4275. [Abstract] [Full Text] [PDF]