Tissue-Specific Deletion of the Retinoblastoma Protein in the Pancreatic β-Cell Has Limited Effects on β-Cell Replication, Mass, and Function

Vasavada, Rupangi C.; Cózar‐Castellano, Irene; Sipula, Darinka; Stewart, Andrew F.

doi:10.2337/db06-0517

Cited by 33 publications

(48 citation statements)

References 54 publications

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“…Rb is thought to be dispensable in mature beta cells, possibly due to compensation by p130 [17,35]. However, deletion of Rb in proliferating pancreatic and duodenal homeobox 1 (PDX1)-positive pancreatic progenitors improved glucose tolerance by persistently increasing neurogenin 3-positive cells that were associated with enhanced beta cell proliferation and differentiation, but disrupted alpha cell differentiation and survival [18].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies showed that Rb plays a critical role during the transition from proliferative to differentiated states, but has a limited role once cells exit the cell cycle and differentiate [15,16]. Thus, Rb plays a reduced essential role in mature pancreatic beta cells [17], whereas disruption of Rb in proliferating progenitors improves glucose tolerance through its divergent role in alpha and beta cells [18].…”

Section: Introductionmentioning

confidence: 99%

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Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Cai

Luk

et al. 2014

Diabetologia

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Aims/hypothesis Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagonlike peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action. Methods We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines. In vivo we examined pancreas-specific Rb knockout, whole-body p107 knockout and Rb/p107 doubleknockout mice.Results Rb, but not p107, was downregulated in response to the GLP-1 analogue, exendin-4, in both alpha and beta cells. Intriguingly, this resulted in opposite outcomes of cell cycle arrest in alpha cells but proliferation in beta cells. Overexpression of Rb in alpha and beta cells abolished or attenuated the effects of exendin-4 supporting the important role of Rb in GLP-1 modulation of cell cycling. Similarly, in vivo, Rb, but not p107, deficiency was required for the beta cell proliferative response to exendin-4. Consistent with this finding, Rb, but not p107, was suppressed in islets from humans with diabetes, suggesting the importance of Rb regulation for the compensatory proliferation that occurs under insulin resistant conditions. Finally, while p107 alone did not have an essential role in islet homeostasis, when combined with Rb deletion, its absence potentiated apoptosis of both alpha and beta cells resulting in glucose intolerance and diminished islet mass with ageing. Conclusions/interpretation We found a central role of Rb in the dual effects of GLP-1 in alpha and beta cells. Our findings highlight unique contributions of individual Rb family members to islet cell proliferation and survival.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Cai

Luk

et al. 2014

Diabetologia

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“…Several studies have attempted to increase endocrine, and particularly β-cell, proliferation through regulation of cell cycle proteins (37,38). Specifically, deletion of the cell cycle regulator Rb in differentiated β-cells did not significantly alter β-cell mass (22). The challenge in defining the role of Rb in different tissues lies in its specificity not only to cell type but also to precise stages in the cellular differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Rb has also been shown to control cell lineage commitment in several cell types, including mesenchymal stem cells (20) and preadipocytes (21). In the pancreas, Rb has been shown to play a minor role in well-differentiated β-cells, as evidenced by mice with rat insulin promoter-Cre-driven Rb deletion (22). However, E2f1 is required for normal pancreatic islet function and homeostasis (23,24).…”

mentioning

confidence: 99%

Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate

Cai

Schroer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic endocrine cells expand rapidly during embryogenesis by neogenesis and proliferation, but during adulthood, islet cells have a very slow turnover. Disruption of murine retinoblastoma tumor suppressor protein (Rb) in mature pancreatic β-cells has a limited effect on cell proliferation. Here we show that deletion of Rb during embryogenesis in islet progenitors leads to an increase in the neurogenin 3-expressing precursor cell population, which persists in the postnatal period and is associated with increased β-cell mass in adults. In contrast, Rb-deficient islet precursors, through repression of the cell fate factor aristaless related homeobox, result in decreased α-cell mass. The opposing effect on survival of Rb-deficient α-and β-cells was a result of opposing effects on p53 in these cell types. As a consequence, loss of Rb in islet precursors led to a reduced α-to β-cell ratio, leading to improved glucose homeostasis and protection against diabetes.diabetes mellitus | insulin | glucagon | cell cycle | E2f

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“…13,14 Nevertheless, there are findings showing that RB1 may be dispensable for cell cycle exit and control of cell growth because it occurs in cardiomyocytes and pancreatic ß-cells. 19,20 Altogether these studies clearly show that RB1 function is context dependent, in some settings RB1, RB2/P130, and P107 can compensate for each other. A functional compensation may occur when one protein is capable of a function usually performed by the other but in normal circumstances does not exercise such a function.…”

Section: Discussionmentioning

confidence: 96%

Mesenchymal stromal cells having inactivated RB1 survive following low irradiation and accumulate damaged DNA: Hints for side effects following radiotherapy

et al. 2017

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Following radiotherapy, bone sarcomas account for a significant percentage of recurring tumors. This risk is further increased in patients with hereditary retinoblastoma that undergo radiotherapy. We analyzed the effect of low and medium dose radiation on mesenchymal stromal cells (MSCs) with inactivated RB1 gene to gain insights on the molecular mechanisms that can induce second malignant neoplasm in cancer survivors.MSC cultures contain subpopulations of mesenchymal stem cells and committed progenitors that can differentiate into mesodermal derivatives: adipocytes, chondrocytes, and osteocytes. These stem cells and committed osteoblast precursors are the cell of origin in osteosarcoma, and RB1 gene mutations have a strong role in its pathogenesis. Following 40 and 2000 mGy X-ray exposure, MSCs with inactivated RB1 do not proliferate and accumulate high levels of unrepaired DNA as detected by persistence of gamma-H2AX foci. In samples with inactivated RB1 the radiation treatment did not increase apoptosis, necrosis or senescence versus untreated cells. Following radiation, CFU analysis showed a discrete number of cells with clonogenic capacity in cultures with silenced RB1.We extended our analysis to the other members of retinoblastoma gene family: RB2/P130 and P107. Also in the MSCs with silenced RB2/P130 and P107 we detected the presence of cells with unrepaired DNA following X-ray irradiation. Cells with unrepaired DNA may represent a reservoir of cells that may undergo neoplastic transformation. Our study suggests that, following radiotherapy, cancer patients with mutations of retinoblastoma genes may be under strict controls to evaluate onset of secondary neoplasms following radiotherapy.

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Tissue-Specific Deletion of the Retinoblastoma Protein in the Pancreatic β-Cell Has Limited Effects on β-Cell Replication, Mass, and Function

Cited by 33 publications

References 54 publications

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate

Mesenchymal stromal cells having inactivated RB1 survive following low irradiation and accumulate damaged DNA: Hints for side effects following radiotherapy

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