Cyclin-dependent kinase 2/cyclin E complex is involved in p120 catenin (p120ctn)-dependent cell growth control: a new role for p120ctn in cancer.
Depending on its cellular localization, p120 catenin (p120ctn) can participate in various processes, such as cadherin-dependent cell-cell adhesion, actin cytoskeleton remodeling, and intracellular trafficking. Recent studies also indicate that p120ctn could regulate cell proliferation and contact inhibition. This report describes a new function of p120ctn in the regulation of cell cycle progression. Overexpression of the p120ctn isoform 3A in human colon adenocarcinoma cells (HT-29) results in cytoplasmic accumulation of the protein, as observed in many tumors. This cytoplasmic increase is correlated with a reduction in proliferation and inhibition of DNA synthesis. Under these conditions, experiments on synchronized cells revealed a prolonged S phase associated with cyclin E stabilization. Both confocal microscopy and biochemical analysis showed that cyclin E and cyclin-dependent kinase 2 colocalized with p120ctn in centrosomes during mitosis. These proteins are associated in a functional complex evidenced by coimmunoprecipitation experiments and the emergence of Thr199-phosphorylated nucleophosmin/B23. Such post-translational modification of this centrosomal target has been shown to trigger the initiation of centrosome duplication. Therefore, p120ctn-mediated accumulation of cyclin E in centrosomes may participate in abnormal amplification of centrosomes and the inhibition of DNA replication, thus leading to aberrant mitosis and polyploidy. Because these modifications are often observed in cancer, p120ctn may represent a new therapeutic target for future therapy.
Chartier
Nicolas T
NT
INSERM U823, Institut Albert Bonniot, Equipe DySAD Site Santé, Grenoble, France.
Oddou
Christiane I
CI
Lainé
Michèle G
MG
Ducarouge
Benjamin
B
Marie
Christiane A
CA
Block
Marc R
MR
Jacquier-Sarlin
Muriel R
MR
D051177:Catenins; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D018385:Centrosome / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D005784:Gene Amplification; D042822:Genomic Instability; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D000095002:Delta Catenin
D051177:Catenins; D015815:Cell Adhesion Molecules; D019927:Cyclin E; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D051357:Cyclin-Dependent Kinase 2; D000095002:Delta Catenin; C000722347:CTNND1 protein, human