c-Myc Controls Proliferation Versus Differentiation in Human Pancreatic Endocrine Cells

Demeterco, Carla

doi:10.1210/jc.87.7.3475

Cited by 20 publications

(22 citation statements)

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“…The overall effect of the absence of Aqp7 was a reduction in TUNEL positivity in the pancreatic islets. The reduction in caspase 3 and Bax is consistent with this effect and also with the known stimulatory effect of c-myc overexpression (7,30). The simultaneous fall in the levels of Bcl2 and Bcl-XL, the antiapoptotic transcripts, could be a compensatory change in response to the reduction in apoptotic gene expression.…”

Section: Proliferation-and Apoptosis-related Gene Expression In Isletsupporting

confidence: 80%

Aquaporin 7 Is a β-Cell Protein and Regulator of Intraislet Glycerol Content and Glycerol Kinase Activity, β-Cell Mass, and Insulin Production and Secretion

Matsumura

Chang

Fujimiya³

et al. 2007

Molecular and Cellular Biology

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To investigate if intracellular glycerol content plays a role in the regulation of insulin secretion in pancreatic ␤ cells, we studied the expression of the glycerol channels, or aquaglyceroporins, encoded by the aquaporin 3 (Aqp3), Aqp7, and Aqp9 genes in mouse islets. We found expression of Aqp7 only, not that of Aqp3 or Aqp9, in the endocrine pancreas at both the mRNA (by reverse transcription-PCR) and protein (by immunohistochemistry) levels. Immunohistochemistry revealed a complete overlap between insulin and Aqp7 immunostaining in the pancreatic islet. Inactivation of Aqp7 by gene targeting produced viable and healthy mice. Aqp7 ؊/؊ mice harbored an increased intraislet glycerol concentration with a concomitant increase of the glycerol kinase transcript level and enzyme activity. The islet triglyceride content in the Aqp7 ؊/؊ mice was also increased compared to that in the Aqp7 ؉/؉ mice. Interestingly, Aqp7 ؊/؊ mice displayed reduced ␤-cell mass and insulin content but increased insulin-1 and insulin-2 mRNAs. The reduction of ␤-cell mass in Aqp7 ؊/؊ mice can be explained at least in part by a reduction in cell proliferation through protein kinase C and the c-myc cascade, with a reduction in the transcript levels of these two genes. Concomitantly, there was a decreased rate of apoptosis, as reflected by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and caspase 3 and Bax expression in Aqp7 ؊/؊ mice. Compared with Aqp7 ؉/؉ islets, islets isolated from Aqp7mice secreted insulin at a higher rate under basal low-glucose conditions and on exposure to a high (450 mg/dl) glucose concentration. Aqp7 ؊/؊ mice exhibited normal fasting blood glucose levels but elevated blood insulin levels. Their plasma glucose response to an intraperitoneal (i.p.) glucose tolerance test was normal, but their plasma insulin concentrations were higher than those of wild-type mice during the 2-h test. An i.p. insulin tolerance test showed similar plasma glucose lowering in Aqp7 ؊/؊ and Aqp7 ؉/؉ mice, with no evidence of insulin resistance. In conclusion, we found that pancreatic ␤ cells express AQP7, which appears to be a key regulator of intraislet glycerol content as well as insulin production and secretion.Glucose is the most important nutrient that regulates insulin secretion (21). In addition to its key role in insulin secretion, plasma glucose also regulates ␤-cell mass; in insulin-resistant states, the ␤-cell mass increases to provide sufficient insulin to keep the plasma glucose concentration in check. Therefore, glucose appears to play dual roles as a stimulus both for acute insulin secretion and for a compensatory increase in ␤-cell mass (8). Unlike glucose, glycerol, a triose sugar, has no apparent effect on insulin secretion (37, 39), though a closely related metabolite, glyceraldehyde, has a potent effect (1, 2). One reason that glycerol does not function as a signal for insulin secretion is that it appears not to be metabolized by pancreatic ␤ cells (37). Induced overexpression of glycerol kina...

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Section: Proliferation-and Apoptosis-related Gene Expression In Isletsupporting

confidence: 80%

Aquaporin 7 Is a β-Cell Protein and Regulator of Intraislet Glycerol Content and Glycerol Kinase Activity, β-Cell Mass, and Insulin Production and Secretion

Matsumura

Chang

Fujimiya³

et al. 2007

Molecular and Cellular Biology

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“…[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

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“…Since many differences exist between rodent and human β cells, attempts have been made to generate human β cell lines from many human pancreatic sources, such as adult islets, fetal pancreases, or insulinomas. However, insulin production by these cells was extremely low or these cells were capable of producing insulin only over a few passages (10)(11)(12)(13). In 2005, Narushima et al (14) reported that they successfully established a functional human β cell line, NAKT-15.…”

Section: Introductionmentioning

confidence: 99%

A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion

Ravassard¹,

Hazhouz²,

Pechberty³

et al. 2011

J. Clin. Invest.

522

521

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Despite intense efforts over the past 30 years, human pancreatic β cell lines have not been available. Here, we describe a robust technology for producing a functional human β cell line using targeted oncogenesis in human fetal tissue. Human fetal pancreatic buds were transduced with a lentiviral vector that expressed SV40LT under the control of the insulin promoter. The transduced buds were then grafted into SCID mice so that they could develop into mature pancreatic tissue. Upon differentiation, the newly formed SV40LT-expressing β cells proliferated and formed insulinomas. The resulting β cells were then transduced with human telomerase reverse transcriptase (hTERT), grafted into other SCID mice, and finally expanded in vitro to generate cell lines. One of these cell lines, EndoC-βH1, expressed many β cell-specific markers without any substantial expression of markers of other pancreatic cell types. The cells secreted insulin when stimulated by glucose or other insulin secretagogues, and cell transplantation reversed chemically induced diabetes in mice. These cells represent a unique tool for large-scale drug discovery and provide a preclinical model for cell replacement therapy in diabetes. This technology could be generalized to generate other human cell lines when the cell type-specific promoter is available.

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c-Myc Controls Proliferation Versus Differentiation in Human Pancreatic Endocrine Cells

Cited by 20 publications

References 0 publications

Aquaporin 7 Is a β-Cell Protein and Regulator of Intraislet Glycerol Content and Glycerol Kinase Activity, β-Cell Mass, and Insulin Production and Secretion

Aquaporin 7 Is a β-Cell Protein and Regulator of Intraislet Glycerol Content and Glycerol Kinase Activity, β-Cell Mass, and Insulin Production and Secretion

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

A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion

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