PMID- 19190347
OWN - NLM
STAT- MEDLINE
DCOM- 20090324
LR  - 20211203
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 69
IP  - 4
DP  - 2009 Feb 15
TI  - Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor 
      overexpression in pancreatic adenocarcinoma through protein kinase Cdelta.
PG  - 1350-7
LID - 10.1158/0008-5472.CAN-08-1328 [doi]
AB  - Pancreatic adenocarcinoma (PCA) is an almost invariably fatal disease. Recently, 
      it has been shown by several groups as well as ours that insulin-like growth 
      factor-I receptor (IGF-IR) overexpression is related to higher proliferation, 
      survival, angiogenesis, and highly invasive pancreatic tumors. Several studies 
      have been carried out to understand the pathways that lead to growth 
      factor-mediated signaling, but the molecular mechanism of receptor overexpression 
      remains mostly unknown. Treatment with neutralizing antibodies or a specific 
      kinase inhibitor against IGF-IR could block the receptor expression in PCA cells. 
      Furthermore, we also showed that insulin receptor substrate (IRS)-2, but not 
      IRS-1, is involved in regulation of IGF-IR expression, which is most likely not 
      transcriptional control. By blocking mammalian target of rapamycin (mTOR) pathway 
      with rapamycin as well as other biochemical analysis, we defined a unique 
      regulation of IGF-IR expression mediated by protein kinase Cdelta (PKCdelta) and 
      mTOR pathway. Moreover, we showed that the down-regulation of IGF-IR expression 
      due to IRS-2 small interfering RNA can be compensated by overexpression of 
      dominant-active mutant of PKCdelta, suggesting that PKCdelta is downstream of 
      IGF-IR/IRS-2 axis. Overall, these findings suggest a novel regulatory role of 
      IRS-2 on the expression of IGF-IR through PKCdelta and mTOR in pancreatic cancer 
      cells.
FAU - Kwon, Junhye
AU  - Kwon J
AD  - Department of Biochemistry and Molecular Biology, Mayo Clinic College of 
      Medicine, Rochester, Minnesota 55905, USA.
FAU - Stephan, Susann
AU  - Stephan S
FAU - Mukhopadhyay, Ananya
AU  - Mukhopadhyay A
FAU - Muders, Michael H
AU  - Muders MH
FAU - Dutta, Shamit K
AU  - Dutta SK
FAU - Lau, Julie S
AU  - Lau JS
FAU - Mukhopadhyay, Debabrata
AU  - Mukhopadhyay D
LA  - eng
GR  - R01 CA078383-10/CA/NCI NIH HHS/United States
GR  - R01 HL072178-06/HL/NHLBI NIH HHS/United States
GR  - R01 HL072178/HL/NHLBI NIH HHS/United States
GR  - R01 HL070567-07/HL/NHLBI NIH HHS/United States
GR  - R29 CA078383/CA/NCI NIH HHS/United States
GR  - HL70567/HL/NHLBI NIH HHS/United States
GR  - CA78383/CA/NCI NIH HHS/United States
GR  - R01 CA078383/CA/NCI NIH HHS/United States
GR  - R01 HL070567/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090203
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (DNA Primers)
RN  - 0 (IRS1 protein, human)
RN  - 0 (IRS2 protein, human)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C-delta)
SB  - IM
MH  - Adenocarcinoma/enzymology/*genetics/physiopathology
MH  - Cell Division
MH  - Cell Line, Tumor
MH  - DNA Primers
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Insulin Receptor Substrate Proteins/*physiology
MH  - Neoplasm Invasiveness
MH  - Neovascularization, Pathologic
MH  - Pancreatic Neoplasms/enzymology/*genetics/physiopathology
MH  - Polymerase Chain Reaction
MH  - Protein Biosynthesis
MH  - Protein Kinase C-delta/*genetics/metabolism
MH  - Protein Kinases/physiology
MH  - RNA, Neoplasm/genetics
MH  - RNA, Small Interfering/genetics
MH  - Receptor, IGF Type 1/*genetics
MH  - TOR Serine-Threonine Kinases
PMC - PMC2705142
MID - NIHMS104096
EDAT- 2009/02/05 09:00
MHDA- 2009/03/25 09:00
PMCR- 2010/02/15
CRDT- 2009/02/05 09:00
PHST- 2009/02/05 09:00 [entrez]
PHST- 2009/02/05 09:00 [pubmed]
PHST- 2009/03/25 09:00 [medline]
PHST- 2010/02/15 00:00 [pmc-release]
AID - 0008-5472.CAN-08-1328 [pii]
AID - 10.1158/0008-5472.CAN-08-1328 [doi]
PST - ppublish
SO  - Cancer Res. 2009 Feb 15;69(4):1350-7. doi: 10.1158/0008-5472.CAN-08-1328. Epub 
      2009 Feb 3.