CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle.
The Gadd45 family of proteins includes Gadd45alpha, MyD118/Gadd45beta, and CR6/OIG37/Gadd45gamma. These proteins play important roles in maintaining genomic stability and in regulating the cell cycle. This study reports the cloning of a novel protein called CR6-interacting factor 1 (CRIF1) which interacts with Gadd45alpha, MyD118/Gadd45beta, and CR6/OIG37/Gadd45gamma. CRIF1 binds specifically to the Gadd45 family proteins, as determined by an in vitro glutathione S-transferase pull-down assay and an in vivo mammalian cell two-hybrid assay along with coimmunoprecipitation assays. CRIF1 mRNA is highly expressed in the thyroid gland, heart, lymph nodes, trachea, and adrenal tissues. CRIF1 localizes exclusively to the nucleus and colocalizes with Gadd45gamma. Recombinant CRIF1 inhibits the histone H1 kinase activity of immunoprecipitated Cdc2-cyclin B1 and Cdk2-cyclin E, and the inhibitory effects were additive with Gadd45 proteins. Overexpression of CRIF1 increases the percentage of cells in G1, decreases the percentage of cells in S phase, and suppresses growth in NIH3T3 cells. The down-regulation of endogenous CRIF1 by the transfection of the small interfering RNA duplexes resulted in the inactivation of Rb by phosphorylation and decreased the G1 phase cell populations. Expression of CRIF1 is barely detectable in adrenal adenoma and papillary thyroid cancer and much lower than in adjacent normal tissue. The results presented here suggest that CRIF1 is a novel nuclear protein that interacts with Gadd45 and may play a role in negative regulation of cell cycle progression and cell growth.
Chung
Hyo Kyun
HK
Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Chungnam National University School of Medicine, Daejeon 301-721 Korea.
Yi
Yong-Weon
YW
Jung
Neon-Cheol
NC
Kim
Daegun
D
Suh
Jae Mi
JM
Kim
Ho
H
Park
Ki Cheol
KC
Song
Jung Hun
JH
Kim
Dong Wook
DW
Hwang
Eun Suk
ES
Yoon
Soo-Hyun
SH
Bae
Young-Seuk
YS
Kim
Jin Man
JM
Bae
Insoo
I
Shong
Minho
M
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000737:chemistry; D002455:Cell Division; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D016193:G1 Phase; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D000097642:GADD45 Proteins
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D005982:Glutathione Transferase; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D000097642:GADD45 Proteins; C485654:GADD45G protein, human; C476586:GADD45GIP1 protein, human