Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130

Abstract

The retinoblastoma gene family consists of three genes: RB, p107, and p130. While loss of pRB causes retinoblastoma in humans and pituitary gland tumors in mice, tumorigenesis in other tissues may be suppressed by p107 and p130. To test this hypothesis, we have generated chimeric mice from embryonic stem cells carrying compound loss-of-function mutations in the Rb gene family. We found that Rb/p107-and Rb/p130-deficient mice were highly cancer prone. We conclude that in a variety of tissues tumor development by loss of pRB is suppressed by its homologs p107 and p130. The redundancy of the retinoblastoma proteins in vivo is reflected by the behavior of Rb-family-defective mouse embryonic fibroblasts in vitro.[Keywords: Retinoblastoma; cancer; mouse model; pocket proteins] Supplemental material is available at http://www.genesdev.org. Inactivation of the retinoblastoma suppressor pRB has been found in many human cancers, including hereditary retinoblastoma and sporadic breast, bladder, prostate, and small cell lung carcinoma (Friend et al. 1986(Friend et al. , 1987Harbour et al. 1988;Lee et al. 1988;T'Ang et al. 1988;Bookstein et al. 1990). pRB controls the G 1 /S transition of the cell cycle by modulating the activity of E2F transcription factors. Hypophosphorylated pRB binds to E2Fs and forms complexes harboring chromatin remodeling proteins like histone deacetylases, SWI/SNF and histone methyltransferases, which actively repress genes that are essential for cell cycle regulation, DNA replication, DNA repair, G 2 /M checkpoints and differentiation (Harbour and Dean 2000;Muller et al. 2001;Ishida et al. 2001;Kalma et al. 2001;Rayman et al. 2002;Ren et al. 2002). Upon sequential phosphorylation by Cyclin D/CDK4 and Cyclin E/CDK2 kinases, pRB undergoes a conformational change leading to the release of E2Fs. Ink4A function has been found in melanoma, pancreatic, and bladder carcinomas, amplification of Cyclin D1 in breast, oesophagus, and head-andneck cancer, and CDK4 amplification or mutational activation in melanoma (for review, see Sherr 1996).RB is a member of the retinoblastoma gene family that encodes the so-called pocket proteins pRB, p107, and p130 (Ewen et al. 1991;Hannon et al. 1993;Li et al. 1993;Chow and Dean 1996). All three can repress transcription from E2F-responsive promoters (Zamanian and La 1993;Bremner et al. 1995;Starostik et al. 1996) and are regulated by cell-cycle dependent phosphorylation. (Graña et al. 1998;Lundberg and Weinberg 1998;Canhoto et al. 2000;Hansen et al. 2001). Over-expression of each of the pocket proteins results in growth suppression, although not every (tumor) cell type is equally sensitive to each family member (Zhu et al. 1993;Claudio et al. 1994;Beijersbergen et al. 1995). Whereas pRB predominantly binds E2F1, E2F2, and E2F3, p107 and p130 specifically bind E2F4 and E2F5 (Dyson 1998;Trimarchi and Lees 2002) and each of these complexes appears at different stages of the cell cycle: p130/E2F4 is mainly found in G 0 , pRB/E2F in G 0 and G 1 , and p107/E2F in S-phase (Dyson ...

Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage

“…Instead, we presume that the tumorigenic consequences of Rb-loss are suppressed in these cells. It seems likely that other pocket proteins contribute to this suppression, becausee chimeras generated with Rb;p107, but not Rb, mutant ES cells develop osteosarcomas at low frequency (22). In addition, our data underscore the key role of p53 in osteosarcoma development.…”

Retinoblastoma family genes

“…Similarly, Rb þ /À;p130À/À and RbÀ/À;p130À/À chimaeras were also tumor prone. In particular, RbÀ/À;p130À/À mice showed consistent development of retinoblastomas, pheochromocytomas and neuroendocrine hyperplasia in the lungs, suggesting that p130 is particularly important in restraining tumor development in these tissues (Dannenberg et al, 2004).…”

“…For example, the additional loss of p107 in RbÀ/À chimaeric mice is sufficient for development of retinoblastoma (RobanusMaandag et al, 1998). More recently Rb þ /À;p107À/À chimaeras were shown to develop a broad spectrum of tumors, most of which showed loss of the remaining Rb allele, indicating that p107 is an important tumor suppressor in the absence of Rb (Dannenberg et al, 2004). Similarly, Rb þ /À;p130À/À and RbÀ/À;p130À/À chimaeras were also tumor prone.…”

Structural mechanisms of DREAM complex assembly and regulation

“…While p107 and p130 loss in genetic models does not readily lead to tumors, there is evidence that p107 and p130 have tumor suppression function and can compensate for Rb loss in certain contexts (Dannenberg et al 2004;Wirt and Sage 2010). The cBioPortal for Cancer Genomics catalogs a number of missense and nonsense mutations in both p107 and p130 that occur in human cancer samples (Gao et al 2013).…”