title: Aberrant activation of gamma-catenin promotes genomic instability and oncogenic effects during tumor progression.
abstract: Gamma-catenin (plakoglobin) exists in cells either as a component of adherens junctions, along with beta-catenin and alpha-catenin, or in association with desmoplakin in desmosomes, which are in turn coupled to the cytoskeleton linking to the plasma membrane. Although gamma-catenin overexpression is observed in many cancers, the molecular basis of its contribution to tumor progression remains unclear. In this study, we examined gamma-catenin overexpression-mediated effects leading to altered regulation of effector genes such as PTTG and c-Myc, as well as differential activation of signaling pathways. We found that overexpression of gamma-catenin caused: (1) a reduction in E-cadherin and corresponding increase in vimentin levels concomitant with increased cell mobility and migration; (2) enhancement in the levels of phosphorylated Akt and Erk in the presence of EGF and (3) an increase in PTTG and c-Myc protein levels, which are likely to accelerate chromosomal instability and uncontrolled proliferation, respectively, in the affected cells. These effects resulting from overexpression of gamma-catenin were further validated in converse experiments with the aid of siRNA knockdown of the endogenous gamma-catenin gene. In conclusion, our studies provide a molecular basis for the promotion of genomic instability and the oncogenic effects due to overexpression of gamma-catenin in human cancer.
authors.affiliation: Department of Medicine (Genetics Program and Cancer Research Center), Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.forename: Fangming
authors.initials: F
authors.lastname: Gao
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papageorgis
authors.forename: Hamid Mostafavi
authors.initials: HM
authors.lastname: Abdolmaleky
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Faller
authors.forename: Sam
authors.initials: S
authors.lastname: Thiagalingam
mesh_terms: D000782:Aneuploidy; D002465:Cell Movement / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D064249:Securin; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic; D015854:Up-Regulation; D051185:gamma Catenin / Q000378:metabolism*
chemical_list: C489427:MYC protein, human; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D064249:Securin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051185:gamma Catenin; C578002:pituitary tumor-transforming protein 1, human; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3