[Different regulation systems of cell cycle events (dysregulation of these events in the tumoral cell)]

Abstract

Preservation of the shape and the integrity of multicellular eukaryotes needs rigorous cell proliferation monitoring. During the prereplicative G1 phase, a finely adjusted and specific control supervises the proliferant/non proliferant states of the cells. Some molecular mechanisms of growth regulation have been identified in recent years. Changes in normal cell attachment on extracellular matrix and intercellular chemical signalling (secretion of informative molecules) activate intracellular signals for division. The transduction mechanisms of the extracellular signalling to the nucleus have been partially elucidated for steroid hormones and growth factors. Molecular biology research and proto-oncogene discoveries have led to considerable progress in understanding the role of these normal genes in the control of cellular proliferation. The initiation of the response to extracellular factors requires: i), direct transducers (specific binding of the steroid hormone on its cytoplasmic or nuclear receptor and high affinity binding of this activated complex to specific DNA sequences); and ii) indirect transducers (binding of growth factors on extracellular domains of specific receptor proteins which convert this extracellular event into several intracellular signals, secondary messengers, protein kinases and specific nuclear regulatory factors). Whatever the transduction system, nuclear events control transcription of growth regulatory genes. The series of enzymatic reactions set in motion by indirect transduction systems require strict regulation systems, the diversity and the complexity of which has been perceived in studies on jun and fos gene families. Each proliferation step is governed by growth stimulators and growth inhibitors, the transformation of normal cells to cancer cells resulting from alterations of these regulatory process. Independent of extracellular stimuli and of their transfer to the nucleus, intracellular controls coordinate cell cycle phases (G1, S, G2 and M) to produce daughter cells identical to the original cell. Two control points are particularly critical: one in G1 (the "start" point) and the other in G2 just before mitosis. Although intermediate steps between extracellular and intracellular controls are still unknown, yeast gene analyses have allowed determination of molecular regulatory mechanisms implicated in the passage of these critical points. A considerable advance was made by the discovery that some of the involved components presented strong sequence and function homologies in organisms from yeast to man, suggesting a phyllogenetically conserved mechanism. It seems likely that the phosphorylation state of protein p34, its association with a G1-phase specific cyclin or a M-phase specific cyclin, and its protein kinase activity regulate the proliferation state of higher eukaryotic cells. In spite of significant advances, much research is still necessary to elucidate all the mechanisms involved in cell cycle control.