Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity.
Proliferation is the major component for maintenance of beta-cell mass in adult animals. Activation of phosphoinositide 3-kinase/Akt-kinase pathway is a critical regulator of beta-cell mass. Pancreatic beta-cell overexpression of constitutively active Akt in mice (caAkt(Tg)) resulted in marked expansion of beta-cell mass by increase in beta-cell proliferation and size. The current studies provide new insights into the molecular mechanisms involved in beta-cell proliferation by Akt. Proliferation of beta-cells in caAkt(Tg) was associated with increased cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 (cdk4) activity. To determine the role of cdk4 in beta-cell proliferation induced by Akt, we generated caAkt(Tg) mice that were homozygous, heterozygous, or nullizygous for cdk4. The results of these studies showed that deletion of one cdk4 allele significantly reduced beta-cell expansion in caAkt(Tg) mice by decreased proliferation. CaAkt(Tg) mice deficient in cdk4 developed beta-cell failure and diabetes. These experiments suggest that Akt induces beta-cell proliferation in a cdk4-dependent manner by regulation of cyclin D1, cyclin D2, and p21 levels. These data also indicate that alteration in levels of these cell cycle components could affect the maintenance of beta-cell mass in basal states and the adaptation of beta-cells to pathological states resulting in diabetes.
Fatrai
Szabolcs
S
Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Elghazi
Lynda
L
Balcazar
Norman
N
Cras-Méneur
Corentin
C
Krits
Irina
I
Kiyokawa
Hiroaki
H
Bernal-Mizrachi
Ernesto
E
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D056742:Cyclin D2; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D005947:Glucose