Retinoblastoma protein family in cell cycle and cancer: A review

Abstract

Two genes, p107 and Rb2/p130, are strictly related to RB, the most investigated tumor suppressor gene, responsible for susceptibility to retinoblastoma. The products of these three genes, namely pRb, p107, and pRb2/p130 are characterized by a peculiar steric conformation, called "pocket," responsible for most of the functional interactions characterizing the activity of these proteins in the homeostasis of the cell cycle. The interest in these genes and proteins springs from their ability to regulate cell cycle processes negatively, being able, for example, to dramatically slow down neoplastic growth. So far, among these genes, only RB is firmly established to act as a tumor suppressor, because its lack-of-function is clearly involved in tumor onset and progression. It has been found deleted or mutated in most retinoblastomas and sarcomas, but its inactivation is likely to play a crucial role in other types of human cancers. The two other members of the family have been discovered more recently and are currently under extensive investigation. We review analogies and differences among the pocket protein family members, in an attempt to understand their functions in normal and cancer cells.

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins

“…The RB family proteins share a considerable structural homology, primarily at the level of the 'pocket' domain, a complex structure subdivided in A-domain, spacer and B-domain. A-and B-domains are the most conserved among the three RB proteins and are involved in common functional characteristics (Paggi et al, 1996;Mulligan and Jacks, 1998), the most relevant one being the ability to control the cell cycle by negative modulation of the transition between the G1 and S phases (Goodrich et al, 1991;Zhu et al, 1993;Claudio et al, 1994;Starostik et al, 1996). To perform this task, these 'pocket proteins' utilize mechanisms mostly related to inactivation of transcription factors (Kouzarides, 1995), such as those of the E2F family (Cao et al, 1992;Helin et al, 1992Helin et al, , 1993Shirodkar et al, 1992;Beijersbergen et al, 1994;Hijmans et al, 1995;Sardet et al, 1995;Hurford et al, 1997), that promote the cell entrance into the S phase (Ewen, 1994;Weinberg, 1995;Paggi et al, 1996;Mulligan and Jacks, 1998).…”

“…A-and B-domains are the most conserved among the three RB proteins and are involved in common functional characteristics (Paggi et al, 1996;Mulligan and Jacks, 1998), the most relevant one being the ability to control the cell cycle by negative modulation of the transition between the G1 and S phases (Goodrich et al, 1991;Zhu et al, 1993;Claudio et al, 1994;Starostik et al, 1996). To perform this task, these 'pocket proteins' utilize mechanisms mostly related to inactivation of transcription factors (Kouzarides, 1995), such as those of the E2F family (Cao et al, 1992;Helin et al, 1992Helin et al, , 1993Shirodkar et al, 1992;Beijersbergen et al, 1994;Hijmans et al, 1995;Sardet et al, 1995;Hurford et al, 1997), that promote the cell entrance into the S phase (Ewen, 1994;Weinberg, 1995;Paggi et al, 1996;Mulligan and Jacks, 1998). Indeed, in addition to the cell cycle, the RB family proteins regulate a wide spectrum of complex biological phenomena, as differentiation, embryonic development, apoptosis and senescence ( (Riley et al, 1994;Sidle et al, 1996;Herwig and Strauss, 1997;Stiegler et al, 1998;Thomas et al, 2003;Liu et al, 2004;Kapic et al, 2006) and references therein).…”

“…All these three large T-antigens possess a J domain, the homologous of a region conserved among all cellular DnaJ/Hsp40 molecular chaperones, essential for chaperone activity and for the interaction with the DnaK homolog Hsp70/Hsc70 chaperone machinery Kelley and Georgopoulos, 1997;Srinivasan et al, 1997). Simian virus 40, JCV and BKV large T-antigen (LT-Ag) also possess the LxCxE motif, through which they physically interact with all the members of the RB family proteins (Dahiya et al, 2000), which in turn bind to the viral factors through their 'pocket' domain (Paggi et al, 1996;Helt and Galloway, 2003). Binding of LT-Ag, as well as E1A or E7, to the pocket region of the RB proteins results in the physical displacement of physiologically interacting partners, apart from the presence or the absence of a LxCxE motif (e.g.…”

“…Indeed, RB mutations or deletions are shared by several tumor types and, in addition, exogenous expression of wild-type RB in RBdefective cancer cells reverts main characteristics of the neoplastic phenotype ( (Weinberg, 1995;Paggi et al, 1996;Bartek et al, 1997;Kaelin, 1999) …”

Retinoblastoma gene family expression in lymphoid tissues

“…In this region, pRb2/p130 and p107 are much more closely related to each other, with about 50% amino-acid identity, than they are to pRb/p105 (30-35% identity). The pocket region confers a peculiar steric conformation to the RB family members; it is responsible for many protein-protein interactions and characterizes the functional activity of these proteins in the homeostasis of the cell cycle (Ewen et al, 1991;Paggi et al, 1996). A number of common targets have been found to interact with the pocket region, including members of the E2F/DP family of transcription factors, oncoproteins from DNA tumour viruses, the D-type cyclins and the histone deacetylases (Weinberg, 1995;Lee et al, 1998).…”