Ectopic Expression of E2F1 Stimulates Beta-cell Proliferation and Function

Overview

Journal Diabetes

Specialty Endocrinology

Date 2010 Mar 20

PMID 20299467

Citations 16

Authors

Gael Grouwels

Ying Cai

Inge Hoebeke

Gunter Leuckx

Yves Heremans

Ulrike Ziebold

Geert Stange

Marie Chintinne

Zhidong Ling

Daniel Pipeleers

Harry Heimberg

Mark Van de Casteele

Affiliations

Soon will be listed here.

Abstract

Objective: Generating functional beta-cells by inducing their proliferation may provide new perspectives for cell therapy in diabetes. Transcription factor E2F1 controls G(1)- to S-phase transition during the cycling of many cell types and is required for pancreatic beta-cell growth and function. However, the consequences of overexpression of E2F1 in beta-cells are unknown.

Research Design And Methods: The effects of E2F1 overexpression on beta-cell proliferation and function were analyzed in isolated rat beta-cells and in transgenic mice.

Results: Adenovirus AdE2F1-mediated overexpression of E2F1 increased the proliferation of isolated primary rat beta-cells 20-fold but also enhanced beta-cell death. Coinfection with adenovirus AdAkt expressing a constitutively active form of Akt (protein kinase B) suppressed beta-cell death to control levels. At 48 h after infection, the total beta-cell number and insulin content were, respectively, 46 and 79% higher in AdE2F1+AdAkt-infected cultures compared with untreated. Conditional overexpression of E2F1 in mice resulted in a twofold increase of beta-cell proliferation and a 70% increase of pancreatic insulin content, but did not increase beta-cell mass. Glucose-challenged insulin release was increased, and the mice showed protection against toxin-induced diabetes.

Conclusions: Overexpression of E2F1, either in vitro or in vivo, can stimulate beta-cell proliferation activity. In vivo E2F1 expression significantly increases the insulin content and function of adult beta-cells, making it a strategic target for therapeutic manipulation of beta-cell function.

Citing Articles

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life.

Melnik B, Schmitz G Int J Mol Sci. 2022; 23(19).

PMID: 36232796 PMC: 9569743. DOI: 10.3390/ijms231911503.

E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance.

Shirakawa J, Togashi Y, Basile G, Okuyama T, Inoue R, Fernandez M Cell Rep. 2022; 41(1):111436.

PMID: 36198264 PMC: 9617565. DOI: 10.1016/j.celrep.2022.111436.

IL-1beta promotes the age-associated decline of beta cell function.

Boni-Schnetzler M, Mereau H, Rachid L, Wiedemann S, Schulze F, Trimigliozzi K iScience. 2021; 24(11):103250.

PMID: 34746709 PMC: 8554531. DOI: 10.1016/j.isci.2021.103250.

Identification of direct transcriptional targets of NFATC2 that promote β cell proliferation.

Simonett S, Shin S, Herring J, Bacher R, Smith L, Dong C J Clin Invest. 2021; 131(21).

PMID: 34491912 PMC: 8553569. DOI: 10.1172/JCI144833.

Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes.

Cerf M Metabolites. 2020; 10(11).

PMID: 33182622 PMC: 7697558. DOI: 10.3390/metabo10110452.

References

Dimri G, Itahana K, Acosta M, Campisi J . Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol Cell Biol. 1999; 20(1):273-85. PMC: 85083. DOI: 10.1128/MCB.20.1.273-285.2000. View

Cano D, Rulifson I, Heiser P, Swigart L, Pelengaris S, German M . Regulated beta-cell regeneration in the adult mouse pancreas. Diabetes. 2007; 57(4):958-66. DOI: 10.2337/db07-0913. View

Montanya E, Nacher V, Biarnes M, Soler J . Linear correlation between beta-cell mass and body weight throughout the lifespan in Lewis rats: role of beta-cell hyperplasia and hypertrophy. Diabetes. 2000; 49(8):1341-6. DOI: 10.2337/diabetes.49.8.1341. View

Heimberg H, Heremans Y, Jobin C, Leemans R, Cardozo A, Darville M . Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. Diabetes. 2001; 50(10):2219-24. DOI: 10.2337/diabetes.50.10.2219. View

Wu L, Timmers C, Maiti B, Saavedra H, Sang L, Chong G . The E2F1-3 transcription factors are essential for cellular proliferation. Nature. 2001; 414(6862):457-62. DOI: 10.1038/35106593. View

Polager S, Kalma Y, Berkovich E, Ginsberg D . E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Oncogene. 2002; 21(3):437-46. DOI: 10.1038/sj.onc.1205102. View

Polager S, Ginsberg D . E2F - at the crossroads of life and death. Trends Cell Biol. 2008; 18(11):528-35. DOI: 10.1016/j.tcb.2008.08.003. View

Annicotte J, Blanchet E, Chavey C, Iankova I, Costes S, Assou S . The CDK4-pRB-E2F1 pathway controls insulin secretion. Nat Cell Biol. 2009; 11(8):1017-23. PMC: 2824657. DOI: 10.1038/ncb1915. View

Trimarchi J, Lees J . Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol. 2002; 3(1):11-20. DOI: 10.1038/nrm714. View

10.

Wells J, Graveel C, Bartley S, Madore S, Farnham P . The identification of E2F1-specific target genes. Proc Natl Acad Sci U S A. 2002; 99(6):3890-5. PMC: 122619. DOI: 10.1073/pnas.062047499. View

11.

Stanelle J, Stiewe T, Theseling C, Peter M, Putzer B . Gene expression changes in response to E2F1 activation. Nucleic Acids Res. 2002; 30(8):1859-67. PMC: 113199. DOI: 10.1093/nar/30.8.1859. View

12.

Pelengaris S, Khan M, Evan G . Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell. 2002; 109(3):321-34. DOI: 10.1016/s0092-8674(02)00738-9. View

13.

Lomazzi M, Moroni M, Jensen M, Frittoli E, Helin K . Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry. Nat Genet. 2002; 31(2):190-4. DOI: 10.1038/ng891. View

14.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

15.

Heremans Y, Van de Casteele M, Int Veld P, Gradwohl G, Serup P, Madsen O . Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3. J Cell Biol. 2002; 159(2):303-12. PMC: 2173047. DOI: 10.1083/jcb.200203074. View

16.

Butler A, Janson J, Bonner-Weir S, Ritzel R, Rizza R, Butler P . Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2002; 52(1):102-10. DOI: 10.2337/diabetes.52.1.102. View

17.

Scheijen B, Bronk M, van der Meer T, Bernards R . Constitutive E2F1 overexpression delays endochondral bone formation by inhibiting chondrocyte differentiation. Mol Cell Biol. 2003; 23(10):3656-68. PMC: 164752. DOI: 10.1128/MCB.23.10.3656-3668.2003. View

18.

Hallstrom T, Nevins J . Specificity in the activation and control of transcription factor E2F-dependent apoptosis. Proc Natl Acad Sci U S A. 2003; 100(19):10848-53. PMC: 196891. DOI: 10.1073/pnas.1831408100. View

19.

Li F, Zhu J, Tessem J, Beilke J, Varella-Garcia M, Jensen J . The development of diabetes in E2f1/E2f2 mutant mice reveals important roles for bone marrow-derived cells in preventing islet cell loss. Proc Natl Acad Sci U S A. 2003; 100(22):12935-40. PMC: 240722. DOI: 10.1073/pnas.2231861100. View

20.

Fajas L, Annicotte J, Miard S, Sarruf D, Watanabe M, Auwerx J . Impaired pancreatic growth, beta cell mass, and beta cell function in E2F1 (-/- )mice. J Clin Invest. 2004; 113(9):1288-95. PMC: 398423. DOI: 10.1172/JCI18555. View