Rb regulates fate choice and lineage commitment in vivo.
Mutation of the retinoblastoma gene (RB1) tumour suppressor occurs in one-third of all human tumours and is particularly associated with retinoblastoma and osteosarcoma. Numerous functions have been ascribed to the product of the human RB1 gene, the retinoblastoma protein (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 regulators. In addition, pRb has been shown in vitro to regulate several transcription factors that are master differentiation inducers. 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 in vitro. In contrast, pRb acts with E2F to suppress peroxisome proliferator-activated receptor gamma subunit (PPAR-gamma), the master activator of adipogenesis. Because 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, so far, there is no evidence for this in vivo. Here we use mouse models to address this hypothesis in 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.
Calo
Eliezer
E
David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Quintero-Estades
Jose A
JA
Danielian
Paul S
PS
Nedelcu
Simona
S
Berman
Seth D
SD
Lees
Jacqueline A
JA
D002001:Adipose Tissue, Brown / Q000166:cytology* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008067:Lipoma / Q000503:physiopathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology*; D047495:PPAR gamma / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism*; D012509:Sarcoma / Q000503:physiopathology
D050659:Core Binding Factor Alpha 1 Subunit; D047495:PPAR gamma; D016160:Retinoblastoma Protein