Research article summary (published 4 Jul 2009):

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine.

Full Abstract

Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulin-like growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Akt-independent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in beta-catenin (beta-cat) in the nucleus and an increased association between beta-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and beta-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated beta-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear beta-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.

Author information

Author/s: Sun, J (J); Khalid, S (S); Rozakis-Adcock, M (M); Fantus, I G (IG); Jin, T (T);

Affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Oncogene (Oncogene), published in England. (Language: eng)

Reference: 2009-Sep; vol 28 (issue 35) : pp 3132-44

Dates: Created 2009/09/03; Completed 2009/09/22;

PMID: 19581924, status: MEDLINE (last retrieved date: 9/22/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals Cell Line, Tumor Cyclin D1 - metabolism Dose-Response Relationship, Drug Enzyme Activation - drug effects Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; metabolism Female HT29 Cells Humans Insulin - metabolism; pharmacology Intestines - metabolism Mice Mice, Mutant Strains

Mice, Mutant Strains Phosphorylation - drug effects Protein Binding - drug effects Protein Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-myc - metabolism RNA, Small Interfering - metabolism Signal Transduction - drug effects; physiology Time Factors Transfection Wnt Proteins - metabolism beta Catenin - metabolism p21-Activated Kinases - genetics; metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Proto-Oncogene Proteins c-myc (0) ; RNA, Small Interfering (0) ; Wnt Proteins (0) ; beta Catenin (0) ; Insulin (11061-68-0) ; Cyclin D1 (136601-57-5) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.1.37) ; Protein Kinases (EC 2.7.1.37) ; Proto-Oncogene Proteins c-akt (EC 2.7.1.37) ; p21-Activated Kinases (EC 2.7.11.1)

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