Abstract
The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?
Highlights
The textbook model for pRB function is appealingly simple (Fig. 1). pRB is a chromatin-associated protein that limits the transcription of cell cycle genes, primarily via regulation of the E2F transcription factor
The inactivation of pRB compromises the ability of cells to exit the cell cycle, and this places them in a state that is highly susceptible to oncogenic proliferation
E2F is the best-known target of pRB, mapping the genome-wide distribution of pRB on chromatin has been technically challenging
Summary
After the cloning of RB1 (Friend et al 1986; Fung et al 1987; Lee et al 1987), it was discovered that a set of viral oncoproteins directly targets pRB and that these physical interactions were necessary for the transforming properties of the viral products (DeCaprio et al 1988; Whyte et al 1988; Dyson et al 1989). The mitotic defects associated with pRB loss can be suppressed by knockdown of the checkpoint protein Mad (Hernando et al 2004; Sotillo et al 2010; Schvartzman et al 2011), depletion of Wapl (to increase cohesin loading) (Manning et al 2014b), addition of nucleosides (which improves replication dynamics and chromosome cohesion) (Bester et al 2011; Burrell et al 2013; Manning et al 2014a), or manipulations that change chromatin marks at centromeric and pericentromeric heterochromatin (Manning et al 2014b; Tanno et al 2015) These raise the intriguing idea that it may be possible to reduce genome instability caused by RB1 mutation. Moving forward, the key questions will be: Which of these changes are relevant during tumorigenesis and which can be exploited to target cancer cells?
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
