Mutation of
            <i>p107</i>
            exacerbates the consequences of
            <i>Rb</i>
            loss in embryonic tissues and causes cardiac and blood vessel defects

Berman, Seth D.; West, Julie C.; Danielian, Paul S.; Caron, Alicia; Stone, James R.; Lees, Jacqueline A.

doi:10.1073/pnas.0902408106

Cited by 21 publications

(16 citation statements)

References 23 publications

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“…;p130 À/À , and Rb À/À ;p107 À/À ;p130 À/À embryos die earlier during mouse development than Rb À/À embryos, with more pronounced developmental defects, including increased cell death and abnormal proliferation Berman et al 2009;Wirt et al 2010).…”

Section: Retinoblastoma In Humans and Micementioning

confidence: 99%

miR than meets the eye: Figure 1.

Sage¹,

Ventura²

2011

Genes Dev.

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Retinoblastoma is a rare pediatric cancer that has served as a paradigm to investigate the mechanisms of tumorigenesis. In this issue of Genes & Development, Conkrite and colleagues (pp. 1734–1745) found high levels of the miR-17∼92 and miR-106b-25 microRNAs in primary retinoblastomas and show that overexpression of miR-17∼92 accelerates retinoblastoma development in mice by promoting proliferation, in part by reducing expression of the cell cycle inhibitor p21. These experiments identify the RB/miR-17∼92/p21 axis as a critical regulator of retinoblastoma tumorigenesis and potentially many other cancers.

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Section: Retinoblastoma In Humans and Micementioning

confidence: 99%

miR than meets the eye: Figure 1.

Sage¹,

Ventura²

2011

Genes Dev.

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“…Whether adult conduction myocytes were equally affected in this model was not explored. Embryo-restricted loss of Rb in a p107 null background resulted in double outlet right ventricle due to dysregulated proliferation of endothelial and possibly heart mesenchymal cells, but again cardiomyocyte proliferation was normal (Berman et al, 2009). Taken together, these results reinforced the notion that pocket proteins have little to no role in cardiomyocyte or VCS cell cycle arrest during development.…”

Section: Introductionmentioning

confidence: 99%

Pocket proteins critically regulate cell cycle exit of the trabecular myocardium and the ventricular conduction system

et al. 2013

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SummaryDuring development, the ventricular conduction system (VCS) arises from the trabecular or spongy myocardium. VCS and trabecular myocytes proliferate at a significantly slower rate than compact zone myocardial cells, establishing a transmural cell cycle gradient. The molecular determinants of VCS/trabecular myocyte cell cycle arrest are not known. Given the importance of pocket proteins (Rb, p107 and p130) in mediating G0/G1 arrest in many cell types, we examined the role of this gene family in regulating cell cycle exit of the trabecular myocardium and ventricular conduction system. Using a combinatorial knockout strategy, we found that graded loss of pocket proteins results in a spectrum of heart and lung defects. p107/p130 double knockout (dKO) hearts manifest dysregulated proliferation within the compact myocardium and trabecular bases, while the remaining trabecular region cell cycle exits normally. Consequently, dKO hearts exhibit defective cardiac compaction, septal hyperplasia and biventricular outflow tract obstruction, while the VCS appears relatively normal. Loss of all three pocket proteins (3KO) is necessary to completely disrupt the transmural cell cycle gradient. 3KO hearts exhibit massive overgrowth of the trabecular myocardium and ventricular conduction system, which leads to fetal heart failure and death. Hearts carrying a single pocket protein allele are able to maintain the transmural cell cycle gradient. These results demonstrate the exquisite sensitivity of trabecular and conduction myocytes to pocket protein function during ventricular chamber development.

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“…The three pocket proteins also play important, overlapping roles in normal development. Mutation of p107 in the context of Rb mutation exacerbates many of the Rb mutant phenotypes and also elicits novel defects (19–21). Combined germline loss of p107 and p130 causes shorter long bones and reduced endochondral ossification, due to inappropriate proliferation of chondrocytes in the long bone epiphyses (22, 23).…”

Section: Introductionmentioning

confidence: 99%

Loss of pRB and p107 disrupts cartilage development and promotes enchondroma formation

2012

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The pocket proteins pRB, p107, and p130 have established roles in regulating the cell cycle through the control of E2F activity. The pocket proteins regulate differentiation of a number of tissues in both cell cycle-dependent and –independent manners. Prior studies showed that mutation of p107 and p130 in the mouse leads to defects in cartilage development during endochondral ossification, the process by which long bones form. Despite evidence of a role for pRB in osteoblast differentiation, it is unknown whether it functions during cartilage development. Here, we show that mutation of Rb in the early mesenchyme of p107-mutant mice results in severe cartilage defects in the growth plates of long bones. This is attributable to inappropriate chondrocyte proliferation that persists after birth and leads to the formation of enchondromas in the growth plates as early as 8 weeks of age. Genetic crosses show that development of these tumorigenic lesions is E2f3 dependent. These results reveal an overlapping role for pRB and p107 in cartilage development, endochondral ossification and enchondroma formation that reflects their coordination of cell cycle exit at appropriate developmental stages.

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Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

Cited by 21 publications

References 23 publications

miR than meets the eye: Figure 1.

miR than meets the eye: Figure 1.

Pocket proteins critically regulate cell cycle exit of the trabecular myocardium and the ventricular conduction system

Loss of pRB and p107 disrupts cartilage development and promotes enchondroma formation

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