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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review GADD45GIP1 (growth arrest and DNA-damageinducible, gamma interacting protein 1) Kentaro Nakayama, Naomi Nakayama, Tian-Li Wang Departments of Gynecology-Obstetrics and Oncology, Johns Hopkins Medical Institutions, CRBII, Rm: 306, 1550 Orleans Street, Baltimore, MD 21231, USA (KN, NN, TLW) Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/GADD45GIP1ID40668ch19p13.html DOI: 10.4267/2042/44679 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology frame encoding a predicted polypeptide of 222 amino acids with a predicted molecular mass of 25 kDa. In vitro translated Gadd45GIP1 cDNA had an apparent size of 28 kDa. Identity Other names: CKBBP2; CRIF1; MGC4667; MGC4758; PLINP-1; PLINP1; PRG6; Plinp1 HGNC (Hugo): GADD45GIP1 Location: 19p13.13 Local order: Gene orientation: telomere- 3' GADD45GIP1 5'- centromere Description Using a yeast two-hybrid screen to identify human proteins that interact with Gadd45gamma, Chung et al. (2003) identified Gadd45GIP1 in the screen. Gadd45GIP1 interacts with Gadd45 proteins family, which plays an important role in genomic stability, DNA repair, cell cycle regulation, and apoptosis. DNA/RNA Description Expression Gadd45GIP1 gene is encoded by 2 exons located on chromosome 19p13.13. The genomic size is 3078 bp. Gadd45GIP1 is widely expressed in normal tissues, including thyroid, heart, lymph node, trachea, adrenal glands, and ovary. Its expression level is lower in neoplastic tissues. Transcription mRNA size: 744 bp; coding sequence from 25 bp-693 bp. Localisation Protein Mainly located at cell nucleus. Contain nuclear localization signal sequence at its C-terminus domain. Gadd45GIP1 co-localized with Gadd45gamma in the nuclei. Note The Gadd45GIP1 cDNA has a 669 bp open reading Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2) 111 GADD45GIP1 (growth arrest and DNA-damage-inducible, gamma interacting protein 1) phase (Chung et al., 2003). Expression of GADD45GIP1 is found to be down-regulated in several cancers including adrenal adenoma, papillary thyroid cancer, and ovarian cancer (Chung et al., 2003; Nakayama et al., 2007). Therefore, altered expression of GADD45GIP1 may contribute to tumorigenesis of some cell types. More recently, CRIF1 was found to inhibit androgen receptor transactivation through direct physical interaction. Interestingly, CRIF1 represses AR transactivation both by outcompeting AR coactivators and by actively recruiting histone deacetylase (HDAC). Moreover, overexpression of CRIF1 decreases the mRNA level of AR-responsive gene and also inhibits the proliferation and cell cycle progression of prostate cancer cells. The data support the functional role of CRIF1 in prostatic cells (Suh et al., 2008). Using serial analysis of gene expression, NAC1 was found to be significantly overexpressed in ovarian serous carcinomas (Nakayama et al., 2006). Immunohistochemical analysis of ovarian serous carcinomas localized NAC1 to discrete nuclear bodies, and the level of NAC1 expression was found to be correlated with tumor recurrence. Recently, GADD45GIP1 was identified as a NAC1- regulated gene (Nakayama et al., 2007). NAC-1 knockdown induced Gadd45GIP1 expres-sion transcriptionally in both SKOV3 and HeLa cells; on the other hand, engineered expression of NAC-1 in NAC-1-negative RK3E and HEK293 cells suppressed endogenous Gadd45GIP1 expres-sion. Furthermore, induced Gadd45GIP1 expression resulted in growth arrest in SKOV3 and HeLa cells both in vitro and in vivo, suggesting the tumor suppressor role of Gadd45GIP1. Function Using yeast-two hybrid screen to identify novel proteins that bind to Gadd45 gene family, Chung et al. (2003) has identified CR6-interacting factor 1 (CRIF1 or Gadd45GIP1). Gadd45GIP1 inhibits Cdc2-cyclin B1 kinase and histone H1 kinase activity associated with immunoprecipitated Cdk2-cyclin E. Overexpression of CRIF1 inhibits cell cycle progression at G1/S and suppresses growth in NIH3T3 cells. Gadd45GIP1 interacts with the orphan nuclear receptor, Nur77, and inhibits its transactivation (Park et al., 2005). To gain more insight in the function of L2 protein of Human Papillomavirus (HPV), Gornemann et al. (2002) performed yeast two hybrid system to isolate putative cellular interaction partners of L2 protein. One of the proteins, designated PLINP, was found to localize in discrete nuclear domains and colocalized with L2. The L2-interacting protein identified may play a role in the viral life cycle and establishment of viral persistence. Nakayama et al. (2007) identified Gadd45GIP1 as the downstream genes negatively regulated by NAC-1, a member of the BTB/POZ gene family and a transcription repressor, as a gene associated with recurrent ovarian carcinoma after chemo-therapy. Mutations Note There is no report. Implicated in Various cancers Disease Ovarian cancer, prostate cancer, thyroid cancer. Oncogenesis GADD45GIP1 (CRIF1) may play a role in negative regulation of cell cycle progression and cell growth. Down-regulation of GADD45GIP1 (CRIF1) by siRNA induced inactivation of Rb and decreased cells in G1 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2) Nakayama K, et al. References Görnemann J, Hofmann TG, Will H, Müller M. Interaction of human papillomavirus type 16 L2 with cellular proteins: identification of novel nuclear body-associated proteins. Virology. 2002 Nov 10;303(1):69-78 Chung HK, Yi YW, Jung NC, Kim D, Suh JM, Kim H, Park KC, Song JH, Kim DW, Hwang ES, Yoon SH, Bae YS, Kim JM, 112 GADD45GIP1 (growth arrest and DNA-damage-inducible, gamma interacting protein 1) Bae I, Shong M. CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle. J Biol Chem. 2003 Jul 25;278(30):28079-88 Nakayama K, Nakayama N, Wang TL, Shih IeM. NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor. Cancer Res. 2007 Sep 1;67(17):8058-64 Park KC, Song KH, Chung HK, Kim H, Kim DW, Song JH, Hwang ES, Jung HS, Park SH, Bae I, Lee IK, Choi HS, Shong M. CR6-interacting factor 1 interacts with orphan nuclear receptor Nur77 and inhibits its transactivation. Mol Endocrinol. 2005 Jan;19(1):12-24 Suh JH, Shong M, Choi HS, Lee K. CR6-interacting factor 1 represses the transactivation of androgen receptor by direct interaction. Mol Endocrinol. 2008 Jan;22(1):33-46 This article should be referenced as such: Nakayama K, Nakayama N, Davidson B, Sheu JJ, Jinawath N, Santillan A, Salani R, Bristow RE, Morin PJ, Kurman RJ, Wang TL, Shih IeM. A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18739-44 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2) Nakayama K, et al. Nakayama K, Nakayama N, Wang TL. GADD45GIP1 (growth arrest and DNA-damage-inducible, gamma interacting protein 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2):111113. 113