WHAT IS THE RESTRICTION POINT

The restriction point (R) separates two functionally different parts o f G(1) in continuously cycling cells. G(1)-pm represents the postmitot ic interval of G(1) that lasts from mitosis to R. G(1)-ps represents t he pre S phase interval of G(1) that lasts from R to S. G(1)-pm is rem arkably constant in length (its duration is about three hours) in the different cell types studied so far. G(1)-ps, however, varies consider ably, indicating that entry into S is not directly followed after pass age through R. Progression through G(1)-pm requires continuous stimula tion by mitogenic signals (e.g. growth factors) and a high rate of pro tein synthesis. Interruption of the mitogenic signals or moderate inhi bition of protein synthesis leads to a rapid exit from the cell cycle to G(0) in normal (untransformed) cells. Upon restimulation with mitog enic signals, the cell returns to the same point in G(1)-pm from which it left the cell cycle. Thus the cell seems to have a memory for how far it has advanced through G(1)-pm, suggesting that a continuous stru ctural alteration, for example chromatin decondensation, takes place i n G(1). The molecular background to transition from growth factor depe ndence in G(1)-pm to growth factor independence in G(1)-ps (a switch w hich represents commitment to a new cell cycle and passage through R) is still not fully understood. Cyclin-dependent kinase (cdk)-mediated hyperphosphorylation of the retinoblastoma protein (Rb), and concomita nt liberation (and activation) of members of the E2F family of transcr iption factors, are probably important aspects of R control in normal cells. A key component here could be cdk2 activity which is controlled by cyclin E. When cdk2 activity starts to increase rapidly in G(1), d ue to activation of a positive feedback loop, it reaches a critical le vel above which cdk inhibitors (CKls) such as p21 and p27 are outweigh ed; the cell has then become independent of mitogenic and inhibitory s ignals and is committed to a new cell cycle. However, other components are probably also involved in R control. For instance, a 'cryptic' R (a G(1)-pm-like state) can be induced even in tumour cells that do not respond to growth factor starvation or protein synthesis inhibitors, and are therefore probably defective in the cdk-Rb-E2F pathway. Possib ly, a certain degree of chromatin decondensation has to take place aft er mitosis in order to allow transcription of, for example, the cyclin E gene or other critical E2F targets. Although the molecular basis fo r restriction point control still remains unclear, we can expect rapid progress in this important field over the next few years.