| Note | The Gadd45GIP1 cDNA has a 669 bp open reading 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. |
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| 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. |
| Expression | 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. |
| Localisation | Mainly located at cell nucleus. Contain nuclear localization signal sequence at its C-terminus domain. Gadd45GIP1 co-localized with Gadd45gamma in the nuclei. |
| 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 chemotherapy. |
| Note | |
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| Entity | 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 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 expression 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 expression. 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. |
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| CR6-interecting Factor 1 Interacts with Gadd45 Family Proteins and Modulates the Cell Cycle |
| 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, Bae I, Shong M. |
| J Biol Chem. 2003 Jul 25;278(30):28079-88. Epub 2003 Apr 25. |
| PMID 12716909 |
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| Interaction of human papillomavirus type 16 L2 with cellular proteins: identification of novel nuclear body-associated proteins. |
| Gornemann J, Hofmann TG, Will H, Muller M. |
| Virology. 2002 Nov 10;303(1):69-78. |
| PMID 12482659 |
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| NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor. |
| Nakayama K, Nakayama N, Wang TL, Shih IeM. |
| Cancer Res. 2007 Sep 1;67(17):8058-64. |
| PMID 17804717 |
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| CR6-interacting factor 1 interacts with orphan nuclear receptor Nur77 and inhibits its transactivation. |
| 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. |
| Mol Endocrinol. 2005 Jan;19(1):12-24. Epub 2004 Sep 30. |
| PMID 15459248 |
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| CR6-interacting factor 1 represses the transactivation of androgen receptor by direct interaction. |
| Suh JH, Shong M, Choi HS, Lee K. |
| Mol Endocrinol. 2008 Jan;22(1):33-46. Epub 2007 Sep 20. |
| PMID 17885209 |
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