ABSTRACT

Living cells are dynamic - with periodic variations in a multitude of molecules controlling a complex array of transducing networks, with feedback loops, branch  points and multicomponent systems producing a diversity of messages. The Ras and Raf proteins are key elements of the growth factor- stimulated, mitogen-activated protein kinase signal pathway, which controls cell proliferation and differentiation. This cascade is modulated by the actions of protein kinases and phosphoprotein phosphatases. In this article, we will review studies we have undertaken on the temporal organisation of cells, highlighting work relating to kinases and phosphatases and the Ras and Raf proteins, and placing particular emphasis on the control of proliferation and differentiation of leukaemic cells growing in culture. We have demonstrated the occurrence of oscillations in kinase and phosphatase expression and activity. Temporal changes for Ras and Raf have been seen not only for the expression of the proteins, but also for the expression of the respective messenger RNA molecules. The presence of inducers of differentiation can modify the patterns with respect to mean, period and amplitude. Our findings are in accordance with the view that the complex interactions between critical signalling molecules may be regulated by altering the characteristics of the rhythms; an understanding of such effects may be of importance in elucidating the mechanisms involved in the control of cell function and transformation.