the camk4crebirs-2 cascade stimulates proliferation and inhibits apoptosis of β-cellscamk4crebirs-2级联β-cells刺激增殖和抑制细胞凋亡.pdf

The CaMK4/CREB/IRS-2 Cascade Stimulates Proliferation and Inhibits Apoptosis of b-Cells Bo Liu, Helena Barbosa-Sampaio, Peter M. Jones, Shanta J. Persaud*., Dany S. Muller. Diabetes Research Group, School of Medicine, Division of Diabetes Nutritional Sciences, King’s College London, London, United Kingdom Abstract Progressive reduction in b-cell mass is responsible for the development of type 2 diabetes mellitus, and alteration in insulin receptor substrate 2 (IRS-2) abundance plays a critical role in this process. IRS-2 expression is stimulated by the transcription factor cAMP response element-binding protein (CREB) and we recently demonstrated that Ca2+/calmodulin dependent kinase 4 (CaMK4) is upstream of CREB activation in b-cells. This study investigated whether CaMK4 is also a potential target to increase b-cell mass through CREB-mediated IRS-2 expression, by quantifying mouse MIN6 b-cell proliferation and apoptosis following IRS-2 knockdown, CaMKs inhibition and alterations in CaMK4 and CREB expression. Expression of constitutively active CaMK4 (DCaMK4) and CREB (CREBDIEDLM) significantly stimulated b-cell proliferation and survival. In contrast, expression of their corresponding dominant negative forms (DK75ECaMK4 and CREBM1) and silencing of IRS-2 increased apoptosis and reduced b-cell division. Moreover, CREBDIEDLM and CREBM1 expression completely abolished the effects of DK75ECaMK4 and of DCaMK4, respectively. Our results indicate that CaMK4 regulates b-cell proliferation and apoptosis in a CREB-dependent manner and that CaMK4-induced IRS-2 expression is important in these processes. Citation: Liu B, Barbosa-Sampaio H, Jones PM, Persaud SJ, Muller DS (2012) The CaMK4/CREB/IRS-2 Cascade Stimulates Proliferation and Inhibits Apoptosis of b- Cells. PLoS ONE 7(9): e45711.