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01.09.2014 | Article

Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

verfasst von: Linyuan Wang, Cynthia T. Luk, Stephanie A. Schroer, Alannah M. Smith, Xie Li, Erica P. Cai, Herbert Gaisano, Patrick E. MacDonald, Zhenyue Hao, Tak W. Mak, Minna Woo

Erschienen in: Diabetologia | Ausgabe 9/2014

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Abstract

Aims/hypothesis

Diabetes mellitus represents a significant burden on the health of the global population. Both type 1 and type 2 diabetes share a common feature of a reduction in functional beta cell mass. A newly discovered ubiquitination molecule HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as MULE or ARF-BP1]) is a critical regulator of p53-dependent apoptosis. However, its role in islet homeostasis is not entirely clear.

Methods

We generated mice with pancreas-specific deletion of Huwe1 using a Cre-loxP recombination system driven by the Pdx1 promoter (Pdx1cre ⁺ Huwe1 ^fl/fl) to assess the in vivo role of HUWE1 in the pancreas.

Results

Targeted deletion of Huwe1 in the pancreas preferentially activated p53-mediated beta cell apoptosis, leading to reduced beta cell mass and diminished insulin exocytosis. These defects were aggravated by ageing, with progressive further decline in insulin secretion and glucose homeostasis in older mice. Intriguingly, Huwe1 deletion provided protection against genotoxicity, such that Pdx1cre ⁺ Huwe1 ^fl/fl mice were resistant to multiple-low-dose-streptozotocin-induced beta cell apoptosis and diabetes.

Conclusion/interpretation

HUWE1 expression in the pancreas is essential in determining beta cell mass. Furthermore, HUWE1 demonstrated divergent roles in regulating beta cell apoptosis depending on physiological or genotoxic conditions.

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Titel: Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions
verfasst von: Linyuan Wang
Cynthia T. Luk
Stephanie A. Schroer
Alannah M. Smith
Xie Li
Erica P. Cai
Herbert Gaisano
Patrick E. MacDonald
Zhenyue Hao
Tak W. Mak
Minna Woo
Publikationsdatum: 01.09.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 9/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3295-8

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