Tumor suppressor genes in childhood malignancies: A review

Hereditary diseases which predispose neoplastic cell transformation have pr oven to be excellent systems for the identification of tumor suppressors. T he primary mutation is already present at birth (due to the heritable predi sposition) so that the mutations directly responsible for tumorigenesis are more easily identified since a mutant allele of a tumor suppressor gene (T SG) is recessive for cellular malignant transformation.([1-5]) The inactiva tion and errant activation of genes critical in the regulation of cell prol iferation and differentiation are hallmarks of neoplastic transformation. A large number of oncogenes and TSGs have been identified and the intimate s teps in multistage carcinogenesis have been elucidated for a number of mali gnancies. It is clear that TSGs are responsible for tumors from disparate t issues. Furthermore the products of these anti-oncogenes function at a vari ety of levels within the cell (i.e. transcriptional regulation, signal tran sduction, cell-cell interaction). The fact remains that these so-called tum or suppressors have profound and extremely important roles in the regulatio n of normal and neoplastic cellular proliferation and differentiation (dedi fferentiation).([6]) The progression of a cell through the cell cycle is co ntrolled in part by a variety of protein kinases, the activity of which is regulated by a group of proteins called cyclins. Cyclins act in concert wit h the cyclin-dependent kinases (CDKs) to phosphorylate key substrates that facilitate the passage of the cell through each phase of the cell cycle. Du e to their critical regulatory functions, all CDKs represent possible tumor suppressors([7]) Here we review the nature of the critical cell . cycle re gulatory retinoblastoma tumor susceptibility and p53 genes, as well as othe r genes affected during the process of carcinogenesis in various tissues, i ncluding the central nervous system, and conclude with a discussion of the implications of TSGs in the improved diagnosis and therapy of human maligna ncies.