Rb family proteins differentially regulate distinct cell lineages during epithelial development

Abstract

pRb, p107 and p130 are important regulators of cell cycle and have extensive overlapping functions; however, only Rb has been shown to be a bone fide tumor suppressor. Defining the overlapping versus distinct pocket protein functions is therefore an important step to understanding the unique role of Rb. Using lung as a model, the present studies demonstrate that pocket proteins are important not only in regulating cell cycle and survival but also in cell lineage specification. An inducible lung-specific Rb knockout strategy was used to demonstrate that Rb is specifically required for restricting neuroendocrine cell fate despite functional compensation for Rb deficiency in other cell types. Ablation of total Rb family function resulted in opposing effects in specification along distinct cell lineages, providing evidence that pocket proteins inhibit neuroendocrine cell fate while being required for differentiation in other cell types. These findings identify a novel role for pocket proteins in cell fate determination, and establish a unique cell lineage-specific function for Rb that explains, at least in part, why Rb and p16 are inactivated in phenotypically distinct carcinomas.

Retinoblastoma Protein (pRb), but Not p107 or p130, Is Required for Maintenance of Enterocyte Quiescence and Differentiation in Small Intestine

“…This may account for the hyperplasia seen in the villus of pRb-null intestine. The continued cycling of villus cells in pRb-null small intestine also led us to question whether these cells could have abnormal apoptosis, because pRb has been shown to regulate apoptosis in other tissues (22,23). As revealed in Fig.…”

A retinoblastoma ortholog controls stalk/spore preference inDictyostelium

“…Rb may also have additional roles in mammalian differentiation. There are intriguing reports of Rb acting as a 'selector gene', favoring white over brown adipose differentiation (Hansen et al, 2004) or specifically inhibiting neurendocrine cell fate in the lung (Wikenheiser-Brokamp, 2004); the Rb-related gene p130 favors neuronal rather than glial differentiation (Jori et al, 2001). In a particularly fascinating case, pRb may referee the interaction of activin and nodal signaling by competing with goosecoid for binding to the transcription factor PU.1 (Konishi et al, 1999).…”

Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes

“…Moreover, different studies suggest that these pocket proteins are also involved in development and differentiation of various tissues (Puri et al, 2001;Wikenheiser-Brokamp, 2004;Nguyen and McCance, 2005).…”

“…In addition, whereas the pocket proteins appear do not regulate the E2F-responsive genes in a fully redundant manner, these proteins show functional redundancy and compensation at cell cycle level. In fact, it has been reported that fibroblasts lacking either pRb1/p105 or p107/pRb2/p130 maintain the ability to arrest in G0/G1 with respect to fibroblasts lacking all three pocket proteins (Dannenberg et al, 2000;Sage et al, 2000. However, the redundancy and compensation among the pocket proteins observed in mouse fibroblasts in vitro fail to do so in a number of cell types in vivo (Marino et al, 2003;Chen et al, 2004;Ruiz et al, 2004;Wikenheiser-Brokamp, 2004). …”