Expression of AIE-75 PDZ-domain protein induces G2/M cell cycle arrest in human colorectal adenocarcinoma SW480 cells.
AIE-75 has been known as a 75-kDa autoantigen detected in the serum of autoimmune enteropathy (AIE) and as a colon cancer-related antigen, and now designated as a gene causative of Usher syndrome type 1C hereditary syndromic hearing loss. It binds to a novel putative tumor suppressor MCC2 that is homologous to MCC (mutated in colon cancer) through a PSD-95/Dlg/ZO-1 (PDZ) domain. To clarify the functional role in colon cancer cells, we transfected AIE-75 gene into SW480 colon cancer cells which do not express AIE-75. Expression of AIE-75 suppressed growth of SW480 cells in vitro in correlation with the expression levels. It was due mainly to G2/M phase cell cycle arrest associated with mitotic slippage, resulting in emergence of hyperploid giant-nucleated or multi-nucleated cells. Screening of proteins that bound to PDZ domains of AIE-75 by a yeast two hybrid system showed that three serine/threonine phosphatase catalytic subunits (PP2AC-alpha, PP2AC-beta, and PPP6C) could bind to AIE-75. Since PP2AC is known to regulate G2/M checkpoint, we suggest that AIE-75 interacts with PP2AC and prevent cells to transit mitotic phase.
Hirai
Atsuko
A
Divisions of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-0815, Japan.
Tada
Mitsuhiro
M
Furuuchi
Keiji
K
Ishikawa
Susumu
S
Makiyama
Kokonoe
K
Hamada
Jun-ichi
J
Okada
Futoshi
F
Kobayashi
Ichiro
I
Fukuda
Hiroshi
H
Moriuchi
Tetsuya
T
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins; D020869:Gene Expression Profiling; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C118970:USH1C protein, human; D010749:Phosphoprotein Phosphatases