CR6-Interacting Factor 1 Interacts with Orphan Nuclear Receptor Nur77 and Inhibits Its Transactivation

Park, Ki Cheol; Song, Kwang Hoon; Chung, Hyo Kyun; Kim, Ho; Kim, Dong Wook; Song, Jung Hun; Hwang, Eun Suk; Jung, Hwa Jin; Park, Su-Hyeon; Bae, Insoo; Lee, In Kyu; Choi, Hueng‐Sik; Shong, Minho

doi:10.1210/me.2004-0107

Cited by 42 publications

(36 citation statements)

References 34 publications

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“…Besides STAT3, Crif1 has other binding partners, such as all three members, Gadd45a, Gadd45b, and Gadd45g, of the Gadd45 protein family and Nur77 (Chung et al, 2003;Park et al, 2005). Although the early embryonic lethality of the Crif1 À/À mice cannot be explained by the interactions with the Gadd45 family members and Nur77, because their mutant mice are viable and fertile, the more severe phenotypes of Crif1 À/À embryos might be due to the additional dysfunctions of other binding partners, in the absence of STAT3 signalling (Lee et al, 1995;Hollander et al, 1999;Gupta et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Crif1 is a novel transcriptional coactivator of STAT3

Kwon

Koo

Moon

et al. 2008

EMBO J

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Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor that performs a broad spectrum of biological functions in response to various stimuli. However, no specific coactivator that regulates the transcriptional activity of STAT3 has been identified. Here we report that CR6-interacting factor 1 (Crif1) is a specific transcriptional coactivator of STAT3, but not of STAT1 or STAT5a. Crif1 interacts with STAT3 and positively regulates its transcriptional activity. Crif1 À/À embryos were lethal around embryonic day 6.5, and manifested developmental arrest accompanied with defective proliferation and massive apoptosis. The expression of STAT3 target genes was markedly reduced in a Crif1 À/À blastocyst culture and in Oncostatin M-stimulated Crif1-deficient MEFs. Importantly, the key activities of constitutively active STAT3-C, such as transcription, DNA binding, and cellular transformation, were abolished in the Crif1-null MEFs, suggesting the essential role of Crif1 in the transcriptional activity of STAT3. Our results reveal that Crif1 is a novel and essential transcriptional coactivator of STAT3 that modulates its DNA binding ability, and shed light on the regulation of oncogenic STAT3.

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Section: Discussionmentioning

confidence: 99%

“…Crif1 interacts with Gadd45a,b,g, and Nur77, and has been suggested as a potential regulator of cell cycle progression and cell growth (Chung et al, 2003;Park et al, 2005). To determine the role of Crif1 in vivo, we generated mice with a disruption in the gene encoding Crif1.…”

Section: Introductionmentioning

confidence: 99%

Crif1 is a novel transcriptional coactivator of STAT3

Kwon

Koo

Moon

et al. 2008

EMBO J

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“…This in turn down-regulates Gadd45 proteins (28 -30). Gadd45 interacts with Gadd45GIP1 and up-regulates MKK4 through MEKK4/MTK1 activation (31). In this manner, Gadd45 functions as a tumor suppressor (26).…”

Section: Discussionmentioning

confidence: 99%

ABTB/POZGene,NAC-1, a Tumor Recurrence–Associated Gene, as a Potential Target for Taxol Resistance in Ovarian Cancer

Ishibashi

Nakayama²,

Yeasmin³

et al. 2008

Clinical Cancer Research

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Purpose: We previously determined that NAC-1, a transcription factor and member of the BTB/POZ gene family, is associated with recurrent ovarian carcinomas. In the current study, we investigated further the relationship between NAC-1expression and ovarian cancer. Experimental Design: NAC-1expression was assessed by immunohistochemistry, and clinical variables were collected by retrospective chart review. SiRNA system and NAC-1 gene transfection were used to asses NAC-1function inTaxol resistance in vivo. Results: Overexpression of NAC-1 correlated with shorter relapse-free survival in patients with advanced stage (stage III/IV) ovarian carcinoma treated with platinum and taxane chemotherapy. Furthermore, overexpression of NAC-1 in primary tumors predicted recurrence within 6 months after primary cytoreductive surgery followed by standard platinum and taxane chemotherapy. NAC-1 expression levels were measured and compared among the human ovarian cancer cell line (KF28), cisplatin-resistant cell line (KFr13) induced from KF28, and paclitaxel-resistant cell lines (KF28TX and KFr13TX) induced by exposing KF28 and KFr13 to dose-escalating paclitaxel. Overexpression of NAC-1was observed in only theTaxol-resistant KF28TX and KFr13 TX cells but not in KF28 or cisplatin-resistant KFr13 cells. To confirm that NAC-1 expression was related to Taxol resistance, we used two independent but complementary approaches. NAC-1 gene knockdown in both KF28TX and KFr13TX rescued paclitaxel sensitivity. Additionally, engineered expression of NAC-1in RK3E cells induced paclitaxel resistance. Conclusions: These results suggest that NAC-1 regulates Taxol resistance in ovarian cancer and may provide an effective target for chemotherapeutic intervention inTaxol-resistant tumors.

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“…Gadd45GIP1 co-localized with Gadd45g in the nuclei, and recombinant Gadd45GIP1 proteins inhibited histone H1 kinase activity of immunoprecipitated Cdc2/ cyclin B1 and Cdk2/cyclin E. The inhibitory effects were synergistic by Gadd45 proteins. In addition, Gadd45GIP1 interacts with the Orphan nuclear receptor, Nur77, and inhibits its transactivation (28). Biologically, overexpression of Gadd45GIP1 inhibited cellular proliferation in NIH3T3 cells, and Gadd45GIP1 gene knockdown led to the inactivation of the Rb pathway (17).…”

Section: Discussionmentioning

confidence: 99%

NAC-1 Controls Cell Growth and Survival by Repressing Transcription of Gadd45GIP1, a Candidate Tumor Suppressor

Nakayama¹,

Nakayama²,

Wang

et al. 2007

Cancer Research

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Cancer mortality and morbidity are primarily related to recurrent tumors, and characterization of recurrence-associated genes should illuminate fundamental properties of tumor progression and provide new therapeutic targets. We have previously identified NAC-1, a member of the BTB/POZ gene family and a transcription repressor, as a gene associated with recurrent ovarian carcinomas after chemotherapy. We further showed that homodimerization of NAC-1 proteins is essential for tumor growth and survival. In this study, we applied serial analysis of gene expression and identified growth arrest and DNA-damage-inducible 45-; interacting protein (Gadd45GIP1) as one of the downstream genes negatively regulated by NAC-1. NAC-1 knockdown in both SKOV3 and HeLa cells that expressed abundant endogenous NAC-1 induced Gadd45GIP1 expression transcriptionally; on the other hand, engineered expression of NAC-1 in NAC-1-negative RK3E and HEK293 cells suppressed endogenous Gadd45GIP1 expression. In NAC-1-expressing tumor cells, induction of dominant negative NAC-1 conferred a growthinhibitory effect that can be partially reversed by Gadd45GIP1 knockdown. Induced Gadd45GIP1 expression resulted in growth arrest in SKOV3 and HeLa cells both in vitro and in vivo. In summary, NAC-1 contributes to tumor growth and survival by at least inhibiting Gadd45GIP1 expression, which has a tumor suppressor effect in cancer cells. [Cancer Res 2007;67(17):8058-64]

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CR6-Interacting Factor 1 Interacts with Orphan Nuclear Receptor Nur77 and Inhibits Its Transactivation

Cited by 42 publications

References 34 publications

Crif1 is a novel transcriptional coactivator of STAT3

Crif1 is a novel transcriptional coactivator of STAT3

ABTB/POZGene,NAC-1, a Tumor Recurrence–Associated Gene, as a Potential Target for Taxol Resistance in Ovarian Cancer

NAC-1 Controls Cell Growth and Survival by Repressing Transcription of Gadd45GIP1, a Candidate Tumor Suppressor

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