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4o1v

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SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer

Structural highlights

4o1v is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SPOP_HUMAN Inhibits IPF1/PDX1 transactivation of established target promoters, such as insulin, may be by recruiting a repressor complex (By similarity). In complex with CUL3, involved in ubiquitination of BMI1, H2AFY and DAXX, and probably also in ubiquitination and proteasomal degradation of Gli2 or Gli3.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Hypoxic stress and hypoxia-inducible factors (HIFs) play important roles in a wide range of tumors. We demonstrate that SPOP, which encodes an E3 ubiquitin ligase component, is a direct transcriptional target of HIFs in clear cell renal cell carcinoma (ccRCC). Furthermore, hypoxia results in cytoplasmic accumulation of SPOP, which is sufficient to induce tumorigenesis. This tumorigenic activity occurs through the ubiquitination and degradation of multiple regulators of cellular proliferation and apoptosis, including the tumor suppressor PTEN, ERK phosphatases, the proapoptotic molecule Daxx, and the Hedgehog pathway transcription factor Gli2. Knockdown of SPOP specifically kills ccRCC cells, indicating that it may be a promising therapeutic target. Collectively, our results indicate that SPOP serves as a regulatory hub to promote ccRCC tumorigenesis.

SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer.,Li G, Ci W, Karmakar S, Chen K, Dhar R, Fan Z, Guo Z, Zhang J, Ke Y, Wang L, Zhuang M, Hu S, Li X, Zhou L, Li X, Calabrese MF, Watson ER, Prasad SM, Rinker-Schaeffer C, Eggener SE, Stricker T, Tian Y, Schulman BA, Liu J, White KP Cancer Cell. 2014 Apr 14;25(4):455-68. doi: 10.1016/j.ccr.2014.02.007. Epub 2014 , Mar 20. PMID:24656772^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001-7. Epub 2003 Oct 5. PMID:14528312 doi:10.1038/ncb1056
↑ Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. Epub 2005 May 16. PMID:15897469 doi:0408918102
↑ Kwon JE, La M, Oh KH, Oh YM, Kim GR, Seol JH, Baek SH, Chiba T, Tanaka K, Bang OS, Joe CO, Chung CH. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. J Biol Chem. 2006 May 5;281(18):12664-72. Epub 2006 Mar 8. PMID:16524876 doi:10.1074/jbc.M600204200
↑ Li G, Ci W, Karmakar S, Chen K, Dhar R, Fan Z, Guo Z, Zhang J, Ke Y, Wang L, Zhuang M, Hu S, Li X, Zhou L, Li X, Calabrese MF, Watson ER, Prasad SM, Rinker-Schaeffer C, Eggener SE, Stricker T, Tian Y, Schulman BA, Liu J, White KP. SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer. Cancer Cell. 2014 Apr 14;25(4):455-68. doi: 10.1016/j.ccr.2014.02.007. Epub 2014 , Mar 20. PMID:24656772 doi:http://dx.doi.org/10.1016/j.ccr.2014.02.007