The retinoblastoma gene family is differentially expressed during embryogenesis

Jiang, Zhe; Zacksenhaus, Eldad; Gallie, Brenda L.; Phillips, Robert A.

doi:10.1038/sj.onc.1201014

Cited by 132 publications

(111 citation statements)

References 27 publications

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“…Recent data have also demonstrated that the di erent pRB-family proteins participate in the regulation of distinct E2F-responsive genes (Hurford et al, 1997). Taken together with their developmentally regulated patterns of expression (Dagnino et al, 1997a,b;Jiang et al, 1997), these experiments predict that the distinct members of the pRB-and E2F-families may not necessarily be redundant and have, in fact, tissue-speci®c roles and/or cell cycle-speci®c activities.…”

Section: Discussionmentioning

confidence: 94%

“…However, E2F-4 and E2F-5 expression in the same system failed to overcome the block unless they were co-expressed with DP1. Together with the apparent restricted tissue speci®city of expression of some of the E2Fs (Dagnino et al, 1997a,b) and pRB-family proteins (Jiang et al, 1997), these data imply a complex cell cycle regulatory pathway where the speci®c outcomes may vary in di erent tissues and at di erent points during development.…”

Section: Introductionmentioning

confidence: 95%

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The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells

et al. 1998

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We previously demonstrated that P16 Ink4a (p16) expression in p16-de®cient U343 astrocytoma cells causes a G 1 cell cycle arrest, profound changes in cytoskeletal proteins and alterations in expression and activity of the pRB and E2F family proteins. We examine here the e ects of expressing wild type or mutant versions of the downstream targets of p16 in U343 astrocytomas. We ®rst attempted to block proliferation of U343 cells using the dominant mutant of pRB, Dp34. Expression of this mutant in the human osteosarcoma, SAOS-2, potently blocked proliferation but did not a ect the cell cycle of U343 cells. We next showed that expression of E2F-1, E2F-2, E2F-3 and E2F-4 are each able to overcome this p16-dependent cell cycle arrest but exhibit distinct biological activities. Adenoviral-mediated expression of E2F-1, E2F-2, E2F-3, or E2F-4 overcame the p16-dependent cell cycle block and induced alterations in cell morphology. E2F-5, only in conjunction with DP1, promoted cell cycle progression. For both E2F-1 and E2F-2, but not E2F-3 or E2F-5/DP1, cell cycle re-entry was associated with almost quantitative cell death. Only small numbers of dying cells were observed in E2F-4-expressing cultures. Expression of the di erent E2F's altered the expression of distinct sets of cell cycle regulatory proteins. E2F-1 induced endogenous E2F-4 expression and also caused an increase in pRB, p107 and cyclin E levels. Expression of E2F-4 caused a weak increase in E2F-1 levels but also strongly induced pRB, p107, p130 and cyclin E. However, E2F-1 and E2F-4 clearly regulate expression of distinct genes, demonstrated when E2F-4 caused a threefold increase in the levels of cdk2 whereas E2F-1 failed to increase in this cyclin dependent kinase. Similarly, expression of E2F-1 or E2F-2 were shown to have distinct e ects on the expression of cdk2, cyclin E and pRB despite both of these closely related E2F-family members potently inducing cell death. Thus, E2F-1, E2F-2, E2F-3 and E2F-4 are able to overcome the p16-dependent proliferative block in U343 astrocytoma cells. While overcoming this cell cycle block, each of the E2F's uniquely a ect the expression of a number of cell cycle regulatory proteins and have distinct abilities to promote cell death.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 95%

The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells

et al. 1998

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“…Rb7/7 mutant embryos die at mid-gestation and develop speci®c abnormalities in neurogenesis, erythropoiesis and lens development. The spectrum of defects in Rb7/7 mutant embryos is consistent with the speci®c expression of Rb during embryogenesis in the nervous system, lens, liver and skeletal muscles (Jiang et al, 1997). Analysis of the role of Rb in older embryos was made possible by the use of a mouse Rb minigene, mgRb, which is expressed exclusively in the nervous system and can rescue the neurogenic defects of Rb7/7 embryos (Zacksenhaus et al, 1996).…”

Section: Introductionmentioning

confidence: 95%

E2F1 mediates ectopic proliferation and stage-specific p53-dependent apoptosis but not aberrant differentiation in the ocular lens of Rb deficient fetuses

Liu

Zacksenhaus

2000

Oncogene

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The retinoblastoma tumor suppressor, Rb, is a transcription cofactor that controls cell proliferation, survival and di erentiation. Mutant mouse embryos lacking Rb exhibit ectopic proliferation and apoptosis that are mediated in some tissues by E2F1, a major partner of Rb, and by the p53 tumor suppressor. Whether E2F1 and p53 also mediate the di erentiation defects in Rb mutant embryos is, however, not clear. Here we show that partially rescued mgRb:Rb7/7 mutant fetuses exhibit ectopic lens epithelial cell proliferation, apoptosis and severe cataract. The abnormal cell proliferation and apoptosis were signi®cantly suppressed in the lens of compound mutant fetuses lacking both Rb and E2F1 at embryonic day (E) E15.5. Interestingly however, at E18.5, only ectopic proliferation, not apoptosis, was dramatically reduced in mgRb:Rb7/7:E2F17/7 lenses. In contrast, p53 did not exert such a stage-speci®c e ect and apoptosis was invariably suppressed in mgRb:Rb7/7:p537/7 composite mutant lenses throughout embryogenesis. Using RT ± PCR and in situ hybridization analyses, we identi®ed a subset of lens speci®c genes, most notably the late di erentiation marker ®lensin, which were not properly induced during lens development in mgRb:Rb7/7 fetuses. Remarkably, despite the inhibition of cell proliferation and apoptosis, the degeneration of lens ®bers and aberrant expression of ®lensin were only marginally corrected in mgRb:Rb7/7:E2F17/7 fetuses at E15.5 but not at all at E18.5 or in mgRb:Rb7/7:p537/7 mutant fetuses. Thus, inactivation of E2F1 reduces ectopic cell proliferation and stage-speci®c p53-dependent apoptosis but does not rescue the di erentiation defects associated with loss of Rb during lens development.

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“…Mice Pancreas-specific Rb knockout mice, Pdx1-Cre:Rb fl/fl (p-RbKO) [18], were bred to p107 −/− whole-body knockout mice (p107KO) (E. Zacksenhaus, Toronto, ON, Canada) [19] to generate Pdx1-Cre:Rb fl/fl /p107 −/− mice (p-DKO) and control Pdx1-Cre:Rb +/+ /p107 +/+ littermates. Mice were maintained on a mixed C57BL6;129/Sv background and housed as previously described [18].…”

Section: Methodsmentioning

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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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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The retinoblastoma gene family is differentially expressed during embryogenesis

Cited by 132 publications

References 27 publications

The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells

The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells

E2F1 mediates ectopic proliferation and stage-specific p53-dependent apoptosis but not aberrant differentiation in the ocular lens of Rb deficient fetuses

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

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