Regulation of the turnover of mRNAs encoding cellular oncoproteins

Abstract

Since the discovery of cellular oncogenes more than a decade ago, important strides have been made in understanding their role in neoplastic transformation. It is proposed that the balance between the oncogene(s) and the tumor suppressor gene(s) (also called anti-oncogene or recessive oncogene) normally govern cell growth. They are the key participants in the major growth-signaling pathways and are instrumental in directing a cell through the various phases of the cell cycle. Therefore, any deviation from normal function of these two sets of interacting genes could lead to oncogenicity. In this context oncogenes are dominant genetic elements representing activation of normal protooncogenes, leading towards malignancy. In contrast, antioncogenes perform a normal regulatory role that is negated by the loss or inactivation of the gene in neoplasia. Recent work has provided insight into the molecular and cellular mechanisms that govern the full malignant phenotype, and it seems clear that oncogenes and anti-oncogenes have an indispensable role to play in solving the puzzle of multistep mammalian carcinogenesis . Proto-oncogene(s) (a normal gene that can be activated to become an oncogene) functions within the complex pathways of signal transduction, which involve the transfer of growth and differentiation signals into a specific program of gene expression. These transformations are brought about by constitutive unregulated stimulation of a receptor that would normally signal proliferation of the target cell. The role of oncogenes as possible regulators of posttranscriptional nuclear events (capping, methylation, splicing, polyadenylation, and formation of ribonucleoprotein complexes), mRNA transport, mRNA stability, and posttranslational feedback mechanisms is still not clear. Furthermore, the relationship between the size of a transcript and the kinetics of degradation remains to be established. Inhibitors of transcription and translation, often used to study mRNA decay, are known to affect the normal turnover of a given mRNA. The discovery of the complex events involved in the regulation of gene expression clearly demonstrates that the intricacies of mRNA turnover have been underestimated. A complete understanding of the mechanisms involved in mRNA maturation and translocation will be required before we have a working model of mRNA longevity. It is now a well-established fact that the rate of synthesis of any protein is directly proportional to the quantity of its mRNA. Recent evidence suggests that apart from transcription, subsequent post-transcriptional mechanisms play an important role in controlling the steady-state levels of