NDRG2 suppresses cell proliferation through down-regulation of AP-1 activity in human colon carcinoma cells.
Recently, the anti-tumor activity of N-myc downstream-regulated gene 2 (NDRG2) was elucidated, but the molecular mechanism of how NDRG2 works as a tumor suppressor is not well known. To determine the function of NDRG2 as a tumor suppressor, we established stable cell lines expressing NDRG2 protein or its mutant forms, and studied their effects on tumor cell growth. Interestingly, constitutive expression of wild-type NDRG2 induced the growth retardation of SW620 colon carcinoma cells. Introduction of NDRG2 into SW620 cells induced the decrease of c-Jun phosphorylation at Ser63, followed by the attenuation of activator protein-1 (AP-1) function as a transcriptional activator. Subsequently, the down-regulation of cyclin D1, which is known as a major target for AP-1 transcription activator, resulted in cell cycle arrest at G1/S phase. Additionally, treatment of NDRG2-siRNA on NDRG2-expressing cells has induced the recovery of c-Jun phosphorylation and cyclin D1 expression. Cell proliferation of those cells was also increased compared with untreated cells. NDRG2 mutants of which the phosphorylation sites at C-terminal region were removed by deletion or site-directed mutagenesis have shown no effect on cyclin D1 expression and could not induce cell growth retardation. In conclusion, NDRG2 modulates intracellular signals to control cell cycle through the regulation of cyclin D1 expression via phosphorylation pathway.
Kim
Young Jun
YJ
Stem Cell Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea. wjkim@kribb.re.kr
Yoon
Sun Young
SY
Kim
Jong-Tae
JT
Choi
Seung Cheol
SC
Lim
Jong-Seok
JS
Kim
Joo Heon
JH
Song
Eun Young
EY
Lee
Hee Gu
HG
Choi
Inpyoi
I
Kim
Jae Wha
JW
D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; C466228:NDRG2 protein, human; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1