The retinoblastoma gene family: its role in cancer onset and progression

In the recent past, a considerable amount of scientific literature has revealed impressive mechanisms that exist to safeguard development and homeostasis in high eukaryotes, and has identified a complex molecular machinery regulating proliferation, differentiation and cell death in mammalian cells. Alteration in at least two of these regulatory circuits is essential for transforming normal cells into malignant ones. During the second half of this century, research focused on the identification and characterisation of genes directly involved in malignant transformation and emphasised that tumourigenesis in humans is the result of a multi-step process reflecting genetic alterations, progressively pushing normal cells towards highly malignant derivatives. Because several human tumours involve loss of heterozygosity of tumour suppressor genes, it is now well accepted that mutations of these genes play a key role in malignant transformation. Current approaches in molecular research have aimed at developing more efficient therapies based on restoring the lost function of genes directly involved in malignant transformation. Since the retinoblastoma (RB) gene family, pRb/p105, pRb2/p130 and p107, has been shown to suppress neoplastic growth, these tumour suppressor genes offer an attractive therapeutic target for treating disorders involving cell growth. This review examines the functional regions of RB family members and the involvement of these genes in controlling cell cycle, apoptosis, differentiation and angiogenesis, highlighting the findings of in vitro and in vivo studies, and focusing on the role of RB proteins in tumourigenesis and in the design of potential approaches for gene therapy development.