HES6 reverses nuclear reprogramming of insulin-producing cells following cell fusion

Ball, Andrew J.; Abrahamsson, Annelie; Tyrberg, Björn; Itkin-Ansari, Pamela; Levine, Fred

doi:10.1016/j.bbrc.2007.01.153

Cited by 8 publications

(7 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, pancreatic progenitors are known to have been already specified at the 6-somite stage [52] , [53] and our results suggests that c Hes6-1 is an early marker for these cells, before Pdx1 . This agrees with the findings that mouse Hes6 is also expressed in pancreatic cells and that its overexpression causes up-regulation of Pdx1 expression [54] .…”

Section: Discussionsupporting

confidence: 92%

HES6-1 and HES6-2 Function through Different Mechanisms during Neuronal Differentiation

Vilas‐Boas¹,

Henrique²

2010

PLoS ONE

View full text Add to dashboard Cite

BackgroundNotch signalling plays a central role in the mechanisms regulating neuronal differentiation in the vertebrate nervous system. The transcriptional repressors encoded by Hes genes are the main effectors of this pathway, acting in neural progenitors during the lateral inhibition process to repress proneural genes and inhibit differentiation. However, Hes6 genes seem to behave differently: they are expressed in differentiating neurons and facilitate the activity of proneural genes in promoting neurogenesis. Still, the molecular mechanisms underlying this unique function of Hes6 genes are not yet understood.Methodology/Principal FindingsHere, we identify two subgroups of Hes6 genes that seem conserved in most vertebrate species and characterize a novel Hes6 gene in chicken: cHes6-1. The embryonic expression pattern of cHes6-1 suggests roles for this gene in the formation of the pancreas, nervous system and in the generation of body asymmetry. We show that cHes6-1 is negatively regulated by Notch signalling in the developing embryonic spinal cord and in pancreatic progenitors, but requires Notch for the observed asymmetric expression at the lateral mesoderm. Functional studies by ectopic expression in the chick embryonic neural tube revealed that cHES6-1 up-regulates the expression of cDelta1 and cHes5 genes, in contrast with overexpression of cHES6-2, which represses the same genes. We show that this activity of cHES6-2 is dependent on its capacity to bind DNA and repress transcription, while cHES6-1 seems to function by sequestering other HES proteins and inhibit their activity as transcriptional repressors.Conclusions/SignificanceOur results indicate that the two chick HES6 proteins act at different phases of neuronal differentiation, contributing to the progression of neurogenesis by different mechanisms: while cHES6-2 represses the transcription of Hes genes, cHES6-1 acts later, sequestering HES proteins. Together, the two cHES6 proteins progressively shut down the Notch-mediated progenitor program and ensure that neuronal differentiation can proceed.

show abstract

Section: Discussionsupporting

confidence: 92%

HES6-1 and HES6-2 Function through Different Mechanisms during Neuronal Differentiation

Vilas‐Boas¹,

Henrique²

2010

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…GFP-positive cells, indicating expression from the human insulin promoter-GFP transgene introduced by lentivirus-mediated gene transfer, were visualized by fluorescence microscopy after two days. Cells were then harvested for RNA isolation and determination of insulin mRNA level by quantitative RT-PCR 30 . Palmitate induced a dose-dependent decrease in the number of GFP-positive cells.…”

Section: Figurementioning

confidence: 99%

Identification of Alverine and Benfluorex as HNF4α Activators

et al. 2013

Self Cite

View full text Add to dashboard Cite

The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings and previously unknown to share mechanistic or structural similarity, activated the nuclear receptor transcription factor HNF4α. Both were hits in a high-throughput screen for compounds that reversed the inhibitory effect of the fatty acid palmitate on human insulin promoter activity. Alverine is used in the treatment of irritable bowel syndrome, while benfluorex (Mediator) was used to treat hyperlipidemia and type II diabetes. Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity. Strikingly, alverine and benfluorex have a previously unrecognized structural similarity, consistent with a common mechanism of action. Gene expression and biochemical studies revealed that they both activate HNF4α. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path towards the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4α activators.

show abstract

“…[28][29][30][31][32][33] bHLH proteins form obligate homodimers or heterodimers, which bind to regulatory E-box sequences in the ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

Section: Id3 Upregulates Brdu Incorporation Associated With a Dna Dammentioning

confidence: 99%

Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells

Lee

Hao

Levine

et al. 2011

Islets

Self Cite

View full text Add to dashboard Cite

HES6 reverses nuclear reprogramming of insulin-producing cells following cell fusion

Cited by 8 publications

References 20 publications

HES6-1 and HES6-2 Function through Different Mechanisms during Neuronal Differentiation

HES6-1 and HES6-2 Function through Different Mechanisms during Neuronal Differentiation

Identification of Alverine and Benfluorex as HNF4α Activators

Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells

Contact Info

Product

Resources

About