The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle

The retinoblastoma gene (RB1) was first identified based on its mutation in a rare malignancy of the eye [1,2]. Shortly thereafter, viral oncogenes such as human papilloma virus E7, simian virus TAg, and adenovirus E1A, were discovered to target it for inactivation during cellular transformation [3-5]. Based on sequence similarity, and analogous interactions with viral proteins, two other members of the RB family were identified, RBL1 and RBL2 that code for the p107 and p130 proteins, respectively [6-11]. All three RB family members contain a conserved domain referred to as the 'pocket' that interacts with the LXCXE motif found in viral proteins such as TAg [12]. For this reason the RB family is also frequently called the pocket protein family. Pocket proteins are present and thought to be central to the regulation of proliferation in many diverse organisms [13]. Furthermore, deregulation of cell cycle control in cancer requires the inactivation of their growth regulatory function [14].In cancer, the RB1 gene is most frequently inactivated through alterations to cyclin dependent kinase regulation, however, in specific cancer types such as small cell lung cancer and retinoblastoma it is uniformly abrogated by direct mutation [15,16]. Reports of cancer derived mutations in the other RB family genes are less common, nevertheless, experimental models of cancer using mice that are deficient for these genes indicate that RBL1 and RBL2 loss can enhance the cancer phenotype in RB1 mutant animals [17-20]. This suggests that the pocket protein family has a collective role in cell cycle control and tumor suppression. In most cancers, their ability to regulate the cell cycle is likely bypassed by altering their common upstream cyclin dependent kinase regulators [15]. At the same time, differences in cancer derived mutations between these genes suggest there may be important biological differences within the RB family. Research on the pocket proteins has often followed this para