How the other half lives, the amino‐terminal domain of the retinoblastoma tumor suppressor protein

Abstract

The retinoblastoma tumor suppressor gene (RB1) is currently the only known gene whose mutation is necessary and sufficient for the development of a human cancer. Mutation or deregulation of RB1 is observed so frequently in other tumor types that compromising RB1 function may be a prerequisite for malignant transformation. Identifying the molecular mechanisms that provide the basis for RB1-mediated tumor suppression has become an important goal in the quest to understand and treat cancer. The lion's share of research on these mechanisms has focused on the carboxy-terminal half of the RB1 encoded protein (pRB). This focus is with good reason since this part of the protein, now called the ''large pocket,'' is required for most of its known activities identified in vitro and in vivo. Large pocket mediated mechanisms alone, however, cannot account for all observed properties of pRB. The thesis presented here is that the relatively uncharacterized amino-terminal half of the protein makes important contributions to pRB-mediated tumor suppression. The goals of this review are to summarize evidence indicating that an aminoterminal structural domain is important for pRB function and to suggest a general hypothesis as to how this domain can be integrated with current models of pRB function.

RB Reversibly Inhibits DNA Replication via Two Temporally Distinct Mechanisms

“…Lastly, it has been recently shown that the RB protein can be detected at sites of replication initiation during the inhibition of replication following DNA damage (4). Based on these studies, it would be predicted that RB could function in cis to inhibit DNA replication potentially dependent on the N terminus of RB (24,25). We failed to observe replicative inhibition by RB in in vitro replication assays with both Nterminal-truncated and full-length RB alleles, although these alleles clearly inhibited DNA replication in cell culture.…”

A retinoblastoma ortholog controls stalk/spore preference inDictyostelium

“…In northern blots, the rblA mRNA was replaced by a ~1.2 kb truncated message fragment (not shown). If this is translated, the product would be a fragment of the N-terminal domain, which in pRb inhibits substrate binding (Goodrich, 2003), and is not predicted to lead to a partial-activity phenotype. Nonetheless, there is a formal possibility that some features of the null phenotype result from this message.…”

The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas

“…Inframe deletions and mutations have also been found in Rb exons 6 and 8 in prostate cancers and astrocytomas, respectively (15, 16). Furthermore, in contrast to pocket mutations, N-terminal inframe deletions in Rb generally display partial penetrance for the development of retinoblastoma (6,8,(11)(12)(13)(14). For example, transgenic mice expressing Rb proteins with N-terminal in-frame deletions produce a partial-penetrance phenotype for tumor development (7).…”

“…The Rb protein functions to harness a variety of cellular processes important in tumorigenesis, including regulation of the cell cycle, apoptosis, differentiation, stress responses, and DNA replication. The role of Rb in these processes derives to a large extent from interactions of proteins with the C terminus of Rb that contains a large pocket domain (1)(2)(3)(4)(5), and most Rb loss-of-function mutations compromise pocket structure and/or function and are highly penetrant alleles of inherited cancer in humans and mice (6).…”

“…Indeed, nearly 20% of cancer-associated in-frame mutations in Rb are located in the Nterminal region (6). These lesions leave an intact C-terminal pocket and generate stable forms of Rb that bind E2F transcription factors and localize to the nucleus in a fashion similar to that of wild-type Rb (wt-Rb) (6)(7)(8)(9)(10).…”