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PMID: 18180285 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Development of hepatocellular carcinoma in Iqgap2-deficient mice is IQGAP1 dependent.

Molecular and cellular biology ·Vol. 28 ·No. 5 ·2008-03-00 ·Pages 1489-502

Schmidt VA, Chiariello CS, Capilla E, Miller F, Bahou WF

Abstract

IQGAPs are multidomain scaffolding proteins that integrate Rho GTPase and Ca2+/calmodulin signals with cell adhesive and cytoskeletal reorganizational events. Targeted disruption of the murine Iqgap2 gene resulted in the age-dependent development of apoptosis and hepatocellular carcinoma (HCC), characterized by the overexpression of IQGAP1, the loss of membrane E-cadherin expression, the cytoplasmic translocation (and activation) of beta-catenin, and the overexpression of a nuclear target of beta-catenin, cyclin D1. In normal hepatocytes, IQGAP2 was found to exist as one component of a multifunctional scaffolding complex comprising IQGAP1, beta-catenin, and E-cadherin, with no evidence for direct IQGAP1-IQGAP2 interactions. Interbreeding of Iqgap2(-/-) mice into the Iqgap1(-/-) background resulted in the phenotypic correction of the preexisting hepatopathy, decreases in the incidence and sizes of HCC tumors, and the normalization of overall survival rates compared to those of Iqgap2(-/-) mice, suggesting that maximal penetrance of the Iqgap2(-/-) HCC phenotype requires the coordinate expression of IQGAP1. These results identify Iqgap2 as a novel tumor suppressor gene specifically linked to the development of HCC and the activation of the Wnt/beta-catenin signaling pathway, while also suggesting that IQGAP1 and IQGAP2 retain functionally divergent roles in hepatocellular carcinogenesis.

MeSH Terms
Aging/physiology Alkaline Phosphatase/blood Alleles Animals Apoptosis Bilirubin/blood Carcinoma, Hepatocellular/genetics,pathology Crosses, Genetic Electroporation Embryonic Stem Cells/cytology Liver/ultrastructure Liver Neoplasms/genetics,pathology Mice Mice, Inbred C57BL Mice, Knockout Mitochondria, Liver/metabolism,ultrastructure Muscle, Skeletal/ultrastructure Penetrance Reverse Transcriptase Polymerase Chain Reaction Tumor Suppressor Proteins/deficiency,genetics,metabolism ras GTPase-Activating Proteins/metabolism
Chemicals
IQ motif containing GTPase activating protein 1 Iqgap2 protein, mouse Tumor Suppressor Proteins ras GTPase-Activating Proteins Alkaline Phosphatase Bilirubin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Schmidt Valentina A
Division of Hematology, HSC T15, Rm 040, State University of New York at Stony Brook, Stony Brook, NY 11794-8151, USA. [email protected]
Chiariello Carmine S
Capilla Encarnación
Miller Frederick
Bahou Wadie F
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.01090-07
Email
[email protected]
Published
2008-03-00
Epub
2008-00-07
Pages
1489-502
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2258764
Subset
IM
Grants
NIDDK NIH HHS · K01 DK062040 · United States
NHLBI NIH HHS · R01 HL049141 · United States
NIDDK NIH HHS · DK62040 · United States
NHLBI NIH HHS · HL49141 · United States
External Links
PubMed source DOI: 10.1128/MCB.01090-07 PMC Full Text View journal details
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