Invited review Oncogenes, growth, and the cell cycle: an overview

In spite of the complexity of the network of regulatory factors which control the balance between the cell cycle and quiescence, a picture is emerging, if only in outline. Several dozens of protooncogenes participate in growth signal transduction and integration, and, when expressed inappropriately, generate growth signals that may override other cellular controls. Some of these controls are provided by the negatively regulating growth factors, and when these are lost (e.g. by chromosomal deletion), or inactivated (e.g. by binding to an inactive analogue or a DNA viral oncoprotein), cell cycle activity is favoured over quiescence. Embryonic tissues are rapidly growing, so their cells are actively cycling and expression of proto-oncogenes is usually observed (Schuuring et al., 1989). As embryonic and stem cells in adult tissues mature, expression of the active proto-oncogenes is generally lost, but other proto-oncogenes may now be expressed (e.g. Muller et al., 1982). These changes in proto-oncogene expression are not achieved by modulation of transcriptional rates alone; transcriptional attenuation, message processing and stability, and post-translational protein modifications are all known to be important for the regulation of proto-oncogene expression during the transition from growth to the differentiated state. When quiescent cells re-enter the cell cycle approximately 60 genes become up-regulated, including proto-oncogene c-fos, the jun family, and c-myc (Zipfel et al., 1989). Evidence is strong that fos and jun proteins are transcriptional regulators. Terminal differentiation, on the other hand, is sometimes accompanied by the up-regulation of the ras gene family, as well as of several other proto-oncogenes. Proto-oncogene function is essential to the cell cycle traverse, but the genes involved are different in various cell types, and the precise order of oncogene expression may not turn out to be important. This is because cell cycle traverse appears to be more dependent on a critical threshold of growth signals propagated by parallel pathways, rather than on a strict order of predetermined steps. The participation of proto-oncogenes in growth signal transduction offers opportunities for errors, and abnormal growth may result from aberrant oncogene products generating a persistent or excessive growth signal, which shifts the balance of input to the integrating genes from quiescence to an active cell cycle. Thus, cancer may result from an entirely normal processing of growth signals that are abnormal.(ABSTRACT TRUNCATED AT 400 WORDS)