Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21 Cip

M Blandino-Rosano, EU Alejandro, A Sathyamurthy… - Diabetologia, 2012 - Springer
M Blandino-Rosano, EU Alejandro, A Sathyamurthy, JO Scheys, B Gregg, AY Chen…
Diabetologia, 2012Springer
Aims/hypothesis The ability of pancreatic beta cells to proliferate is critical both for normal
tissue maintenance and in conditions where there is an increased demand for insulin.
Protein kinase B (Akt) plays a major role in promoting proliferation in many cell types,
including the insulin-producing beta cells. We have previously reported that mice
overexpressing a constitutively active form of Akt (caAkt Tg) show enhanced beta cell
proliferation that is associated with increased protein levels of cyclin D1, cyclin D2 and cyclin …
Aims/hypothesis
The ability of pancreatic beta cells to proliferate is critical both for normal tissue maintenance and in conditions where there is an increased demand for insulin. Protein kinase B (Akt) plays a major role in promoting proliferation in many cell types, including the insulin-producing beta cells. We have previously reported that mice overexpressing a constitutively active form of Akt (caAkt Tg ) show enhanced beta cell proliferation that is associated with increased protein levels of cyclin D1, cyclin D2 and cyclin-dependent kinase inhibitor 1A (p21Cip). In the present study, we sought to assess the mechanisms responsible for augmented p21Cip levels in caAkt Tg mice and test the role of p21Cip in the proliferative responses induced by activation of Akt signalling.
Methods
To gain a greater understanding of the relationship between Akt and p21Cip, we evaluated the mechanisms involved in the modulation of p21Cip by Akt and the in vivo role of reduced p21Cip in proliferative responses induced by Akt.
Results
Our experiments showed that Akt signalling regulates p21 Cip transcription and protein stability. caAkt Tg /p21 Cip+/− mice exhibited fasting and fed hypoglycaemia as well as hyperinsulinaemia when compared with caAkt Tg mice. Glucose tolerance tests revealed improved glucose tolerance in caAkt Tg /p21 Cip+/− mice compared with caAkt Tg . These changes resulted from increased proliferation, survival and beta cell mass in caAkt Tg /p21 Cip+/− compared with caAkt Tg mice.
Conclusions/interpretation
Our data indicate that increased p21Cip levels in caAkt Tg mice act as a compensatory brake, protecting beta cells from unrestrained proliferation. These studies imply that p21Cip could play important roles in the adaptive responses of beta cells to proliferate in conditions such as in insulin resistance.
Springer
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