Reversible immortalization of rat pancreatic β cells with a novel immortalizing and tamoxifen-mediated self-recombination tricistronic vector

Wu, Honglu; Wang, Yu; Zhang, Ping; Li, Shufa; Chen, Xiuping; Chen, Yao-Kai; Li, Jungang; Yang, Shi‐Ming; Su, Yongping; Wang, Junping; Chen, Bing

doi:10.1016/j.jbiotec.2010.12.003

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…TERT can inhibit apoptosis by activating telomerase. TERT overexpression has an antiapoptotic effect on islet β cells, providing a novel target for the treatment of diabetes [ 6 , 7 ]. However, the antiapoptotic mechanism of TERT is unclear.…”

Section: Introductionmentioning

confidence: 99%

TERT and Akt Are Involved in the Par-4-Dependent Apoptosis of Islet β Cells in Type 2 Diabetes

Liu

Lei

et al. 2018

Journal of Diabetes Research

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Islet β cell apoptosis plays an important role in type 2 diabetes. We previously reported that Par-4-mediated islet β cell apoptosis is induced by high-glucose/fatty acid levels. In the present study, we show that Par-4, which is induced by high-glucose/fatty acid levels, interacts with and inhibits TERT in the cytoplasm and then translocates to the nucleus. Par-4 also inhibited Akt phosphorylation, leading to islet β cell apoptosis. We inhibited Par-4 in islet β cells under high-glucose/fatty acid conditions and knocked out Par-4 in diabetic mice, which led to the up-regulation of TERT and an improvement in the apoptosis rate. We inhibited Akt phosphorylation in islet β cells and diabetic mice, which led to aggressive apoptosis. In addition, the biological film interference technique revealed that Par-4 bound to TERT via its NLS and leucine zipper domains. Our research suggests that Par-4 activation and binding to TERT are key steps required for inducing the apoptosis of islet β cells under high-glucose/fatty acid conditions. Inhibiting Akt phosphorylation aggravated apoptosis by activating Par-4 and inhibiting TERT, and Par-4 inhibition may be an attractive target for the treatment of islet β cell apoptosis.

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Section: Introductionmentioning

confidence: 99%

TERT and Akt Are Involved in the Par-4-Dependent Apoptosis of Islet β Cells in Type 2 Diabetes

Liu

Lei

et al. 2018

Journal of Diabetes Research

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“…For example, they upregulate the expression of IAPP (encoding islet amyloid polypeptide), INSULIN, SLC2A2 (encoding the glucose transporter GLUT2), and the ABCC8 and KCNJ11 subunits of the ATP-sensitive potassium channel, which are targets of the sulfonylurea drugs, and they downregulate disallowed genes such as LDH-A and MCT-1 (70). Reversibility of immortalization was previously shown in the mouse β cell line BetaTC-Tet (118) by the shutting off of SV40LT, in rat β cell lines upon Cre-(ER)-mediated excision of SV40LT and hTERT encoding retroviral vectors (119), and in lines of other cell types, such as neurons (120) and cardiomyocytes (121). Some other cell lines, however, succumb to oncogene loss.…”

Section: Reversibility Of Immortalizationmentioning

confidence: 97%

The supply chain of human pancreatic β cell lines

Scharfmann¹,

Staels²,

Albagli³

2019

Journal of Clinical Investigation

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“…The cells produce and secrete high amounts of insulin, and can restore and maintain euglycemia in syngeneic STZ-induced diabetic mice in the absence of dox. Moreover, reversible immortalization of rat pancreatic β-cells has also been reported using tricistronic retroviral vectors, in which Cre-ER, SV40Tag or hTERT and a reporter gene are flanked by the same pair of LoxP sites [25]. The Cre-ER protein was induced to translocate from the cytoplasm to the nucleus by 4-hydroxytamoxifen, in order to excise SV40Tag, hTERT and the Cre-ER gene itself without induced by 90% hepatectomy.…”

Section: Reversibly Immortalized Human Hepatocytesmentioning

confidence: 99%

Controlled Expansion of Mammalian Cell Populations by Reversible Immortalization

Noguchi¹,

Kobayashi²

2013

J Biotechnol Biomaterial

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In 1996, reversible immortalization using SV40 large T antigens and the Cre/LoxP system was successfully achieved with primary human fibroblasts. The concept of reversible immortalization involves introducing an immortalizing agent, SV40 large T antigens, into primary cells, expanding the cells in the culture, and finally, efficiently removing the immortalizing agent using Cre/LoxP site-specific recombination. The resulting cell population is essentially identical to the initial primary cells, but greatly increased in number. Since this report, reversible immortalization has been realized with hepatocytes, pancreatic β-cells, hepatic stellate cells, endothelial cells, renal epithelial cells and myogenic cells. This method facilitates the study of cell transplantation as well as cell differentiation, the cell cycle and senescence, by allowing one to control cell proliferation.

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Reversible immortalization of rat pancreatic β cells with a novel immortalizing and tamoxifen-mediated self-recombination tricistronic vector

Cited by 11 publications

References 38 publications

TERT and Akt Are Involved in the Par-4-Dependent Apoptosis of Islet β Cells in Type 2 Diabetes

TERT and Akt Are Involved in the Par-4-Dependent Apoptosis of Islet β Cells in Type 2 Diabetes

The supply chain of human pancreatic β cell lines

Controlled Expansion of Mammalian Cell Populations by Reversible Immortalization

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