The CaMK4/CREB/IRS-2 cascade stimulates proliferation and inhibits apoptosis of β-cells.
Progressive reduction in β-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 Ca(2+)/calmodulin dependent kinase 4 (CaMK4) is upstream of CREB activation in β-cells. This study investigated whether CaMK4 is also a potential target to increase β-cell mass through CREB-mediated IRS-2 expression, by quantifying mouse MIN6 β-cell proliferation and apoptosis following IRS-2 knockdown, CaMKs inhibition and alterations in CaMK4 and CREB expression. Expression of constitutively active CaMK4 (ΔCaMK4) and CREB (CREB(DIEDLM)) significantly stimulated β-cell proliferation and survival. In contrast, expression of their corresponding dominant negative forms (Δ(K75E)CaMK4 and CREB(M1)) and silencing of IRS-2 increased apoptosis and reduced β-cell division. Moreover, CREB(DIEDLM) and CREB(M1) expression completely abolished the effects of Δ(K75E)CaMK4 and of ΔCaMK4, respectively. Our results indicate that CaMK4 regulates β-cell proliferation and apoptosis in a CREB-dependent manner and that CaMK4-induced IRS-2 expression is important in these processes.
Diabetes Research Group, School of Medicine, Division of Diabetes & Nutritional Sciences, King's College London, London, United Kingdom.
Bo
B
Liu
Helena
H
Barbosa-Sampaio
Peter M
PM
Jones
Shanta J
SJ
Persaud
Dany S
DS
Muller
D000818:Animals; D017209:Apoptosis; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008954:Models, Biological
D017362:Cyclic AMP Response Element-Binding Protein; D055504:Insulin Receptor Substrate Proteins; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse; D005947:Glucose