The rb pathway and cancer therapeutics

Abstract

The retinoblastoma gene, Rb, was originally identified as the tumor suppressor gene mutated in a rare childhood cancer called retinoblastoma (reviewed in [1]). Subsequent studies showed that Rb functions in a pathway that is often functionally inactivated in a large majority of human cancers. Interestingly, recent studies showed that in certain types of cancers, Rb function is actually required for cancer development. The intimate link between the Rb pathway and cancer development suggests that the status of Rb activity can potentially be used to develop targeted therapy. However, a prerequisite will be to understand the role of Rb and its interaction with other signaling pathways in cancer development. In this review, we will discuss the roles of Rb in proliferation, apoptosis and differentiation by reviewing the recent findings in both mammalian systems and different model organisms. In addition, we will discuss strategies that can be employed that specifically target cancer cells based on the status of the Rb pathway.

Fig. (1). The mammalian and Drosophila Rb family proteins

The Rb family of proteins in mammals consists of Rb, p107 and p130, and in Drosophila contains RBF and RBF2. The pocket domain, which is shaded in grey, is conserved and is responsible for most protein-protein interactions. A cyclin/cdk interaction motif (shaded in black) is conserved in the spacer region of p107 and p130 but absent in Rb protein. The activity of Rb proteins is controlled by phosphorylation at numerous phosphorylation sites (indicated for Rb and RBF by *). The phosphorylation sites in other Rb family members have not been precisely mapped.

Fig. (2). Similarities between the Rb and E2F proteins in mammals and Drosophila

In mammals the E2F family is composed of eight E2F proteins, E2F1 through 8 and three DP proteins, DP1, DP2, and DP4. In Drosophila it consists of two E2Fs, dE2F1, dE2F2, and one DP protein, dDP. The eight mammalian E2F proteins can be divided into three groups: activating E2Fs (E2F1, E2F2, and E2F3), repressive E2Fs (E2F4 and E2F5), and Rb independent E2Fs (E2F6, E2F7, and E2F8). The mammalian activating E2Fs interact only with Rb. Similarly, the Drosophila activating E2F, dE2F1, interacts only with RBF. The mammalian repressive E2Fs interact with p107 and p130. In addition, E2F4 can also interact with Rb protein. Similarly, the Drosophila repressive E2F, dE2F2, interacts with both RBF and RBF2.

Fig. (3). The Rb pathway status in cancers and possible therapeutic approaches

There are at least three different functional states of Rb in cancer cells. While a majority of cancers have an inactivated Rb pathway, either by mutation/deletion of Rb or by its functional inactivation (category I and II), a small subset of cancers require functional Rb (category III). Depending on the status of the Rb pathway, different strategies can be potentially used to specifically target cancer cells. See text for more detailed discussion.