PMID- 20427478
OWN - NLM
STAT- MEDLINE
DCOM- 20100705
LR  - 20220330
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Linking)
VI  - 151
IP  - 7
DP  - 2010 Jul
TI  - Role of the TSC1-TSC2 complex in the integration of insulin and glucose signaling 
      involved in pancreatic beta-cell proliferation.
PG  - 3084-94
LID - 10.1210/en.2010-0048 [doi]
AB  - Tuberous sclerosis complex proteins 1-2 (TSC1-TSC2) complex integrates both 
      nutrient and hormonal signaling and is a critical negative regulator of mammalian 
      target of rapamycin (mTOR) complex 1. The use of different beta-cell lines 
      expressing or not the insulin receptor (IR(+/+) and IR(-/-)) or with a 
      reconstituted expression of IR isoform A or B (Rec A and Rec B) revealed that 
      both phosphatidylinositol 3-kinase/Akt/TSC/mTOR complex 1 and MAPK kinase/ERK 
      pathways mediate insulin signaling in IR(+/+)-, IRA-, or IRB-expressing cells. 
      However, glucose signaling was mediated by MAPK kinase/ERK and AMP-activated 
      protein kinase pathways as assessed in IR(-/-) cells. The effect of insulin on 
      Akt phosphorylation was completely inhibited by the use of the 
      phosphatidylinositol 3-kinase inhibitor wortmannin in IR(+/+) and Rec B cells, a 
      partial inhibitory effect being observed in Rec A cell line. The knockdown of 
      TSC2 expression up-regulated the downstream basal phosphorylation of 70-kDa 
      ribosomal protein S6 kinase (p70S6K) and mTOR. More importantly, upregulation of 
      p70S6K signaling impaired insulin-stimulated phosphorylation of Akt Ser(473) and 
      p70S6K in IR(+/+) and Rec B but not in Rec A cell lines. In fact, insulin 
      receptor substrate-1 Ser(307) phosphorylation signal in Rec B was stronger than 
      in Rec A cell line during insulin action. Rec A cells induced a higher 
      proliferation rate compared with Rec B or IR(+/+) during serum stimulation. Thus, 
      we propose that the regulation of TSC2 phosphorylation by insulin or glucose 
      independently integrates beta-cell proliferation signaling, the relative 
      expression of IRA or IRB isoforms in pancreatic beta cells playing a major role.
FAU - Bartolome, Alberto
AU  - Bartolome A
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, 
      Universidad Complutense, 28040 Madrid, Spain.
FAU - Guillen, Carlos
AU  - Guillen C
FAU - Benito, Manuel
AU  - Benito M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100428
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Androstadienes)
RN  - 0 (Insulin)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - IY9XDZ35W2 (Glucose)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Blotting, Western
MH  - Cell Cycle/drug effects
MH  - Cell Line
MH  - Glucose/*pharmacology
MH  - Immunohistochemistry
MH  - Insulin/*pharmacology
MH  - Insulin-Secreting Cells/*drug effects/*metabolism
MH  - Mice
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA, Small Interfering
MH  - Receptor, Insulin/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/genetics/*metabolism
MH  - Wortmannin
EDAT- 2010/04/30 06:00
MHDA- 2010/07/06 06:00
CRDT- 2010/04/30 06:00
PHST- 2010/04/30 06:00 [entrez]
PHST- 2010/04/30 06:00 [pubmed]
PHST- 2010/07/06 06:00 [medline]
AID - en.2010-0048 [pii]
AID - 10.1210/en.2010-0048 [doi]
PST - ppublish
SO  - Endocrinology. 2010 Jul;151(7):3084-94. doi: 10.1210/en.2010-0048. Epub 2010 Apr 
      28.