Rb regulates fate choice and lineage commitment in vivo

Abstract

Mutation of the RB-1 tumour suppressor occurs in one third of all human tumours and is particularly associated with retinoblastoma and osteosarcoma1. Numerous functions have been ascribed to the product of the human RB-1 gene, pRB. The best known is pRB’s ability to promote cell cycle exit through inhibition of the E2F transcription factors and the transcriptional repression of genes encoding cell cycle regulators1. In addition, pRB has been shown in vitro to regulate several transcription factors that are master differentiation inducers2. Depending on the differentiation factor and cellular context, pRB can either suppress or promote their transcriptional activity. For example, pRB binds to Runx2 and potentiates its ability to promote osteogenic differentiation program in vitro3. In contrast, pRB acts together with E2F to suppress PPARγ, the master activator of adipogenesis4,5. Since osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that pRB might play a role in the choice between these two fates. However, to date, there is no evidence for this in vivo. Here we use mouse models to address this hypothesis in the context of mesenchymal tissue development and tumorigenesis. Our data show that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo.

RB1: a prototype tumor suppressor and an enigma

“…This observation adds to a large number of studies showing that, under specific conditions, pRB can cooperate with other factors to promote the transcriptional activation of differentiation programs and regulate the expression of apoptotic regulators (for examples, see Thomas et al 2001;Ianari et al 2009;Calo et al 2010; for review, see Attardi and Sage 2013).…”

“…In addition to the repression of E2F-regulated genes, pRB has been implicated in the organization of chromosomal domains and has roles in gene activation, particularly in response to apoptotic and differentiation signals (Thomas et al 2001;Ianari et al 2009;Calo et al 2010). The RNA signatures associated with RB1 mutation include both up-regulated and down-regulated transcripts (Black et al 2003;Markey et al 2007;Ertel et al 2010).…”

“…In specific compartments, the genetic ablation of RB1 alters cell cycle progression/cell cycle exit, sensitivity to apoptosis, senescence, and differentiation (for review, see Vooijs and Berns 1999;Goodrich 2006;Viatour and Sage 2011;Sage 2012). The mutation of RB1 can alter the type of differentiation programs that are activated, the extent of differentiation that occurs, and the ability of differentiated cells to permanently exit the cell cycle (for examples, see Thomas et al 2001;Calo et al 2010; for review, see Thomas et al 2003;Sage 2012).…”

Brown adipose tissue and bone

“…For example, the transcriptional regulator and tumor suppressor retinoblastoma-associated protein (pRb), has been shown to be an important switch with the potential of directing mesenchymal stem cells toward either an osteoblast or adipocyte lineage. Calo et al 39 showed that pRb directs common mesenchymal precursor cells into an osteoblastic cell fate while inhibiting their differentiation into adipocytes, and that loss of pRb in these precursors greatly increased the presence of BAT at the expense of calcified bone.…”

Retinoblastoma Protein Modulates the Inverse Relationship between Cellular Proliferation and Elastogenesis

“…This sequence is homologous to the DNA sequences capable of interaction with the tumor suppressor retinoblastoma protein (Rb) located in promoters of the multiple genes involved in both cellular proliferation (29 -34) and differentiation (35)(36)(37)(38). This observation was followed by the suggestion that such retinoblastoma control elements (RCE) would also modulate transcription of tropoelastin gene.…”