TBL1XR1 explained

F-box-like/WD repeat-containing protein TBL1XR1 is a protein that in humans is encoded by the TBL1XR1 gene.^{[1] [2] [3]} The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins that appear to have a regulatory function. It is believed that the WD40 repeats mediate protein–protein interactions, and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation.^[3]

Clinical significance

Mutations in TBL1XR1 cause Pierpont syndrome, which involves intellectual disability, a characteristic facial appearance and limb abnormalities.^[4]

Mutations in TBL1XR1 have been identified in lymphomas, including MYD88 wild-type Waldenstrom's macroglobulinemia.^[5]

In prostate cancer, somatic copy-number gains (CNA) in TBL1XR1 are present in around 15% of patients with localised disease, co-occurring with adjacent megagene NAALADL2.^[6] The frequency of CNA gains in these genes associate with a number of clinical features of aggressive prostate cancer including high Gleason grade, tumour stage, positive surgical margins and cancer which has spread to the lymph nodes. The frequency of copy-number gains in this genetic region also increase in castrate resistant and neuroendocrine prostate cancer.

The region surrounding TBL1XR1 is rich in oncogenes.^[7] Copy-number gains in TBL1XR1 often co-occur with neighbouring oncogenes including: BCL6, ATR and PI3K family members. Copy-number gains at the DNA level associate with mRNA expression changes in more than 450 known oncogenes, suggesting this region may be important in driving aggressive prostate cancer. TBL1XR1 is a co-activator of the androgen receptor, a major hormone receptor driving prostate cancer development.^[8] Of the genes whose expression was altered between patients with and without gains, 506 (14.09%) of the genes were androgen-regulated or contained an AR binding site.

Interactions

TBL1XR1 has been shown to interact with nuclear receptor co-repressor 1.^{[9] [10]}

Further reading

• Yoon HG, Chan DW, Huang ZQ, Li J, Fondell JD, Qin J, Wong J . Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1 . The EMBO Journal . 22 . 6 . 1336–46 . March 2003 . 12628926 . 151047 . 10.1093/emboj/cdg120 .
• Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J . N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso . Molecular Cell . 12 . 3 . 723–34 . September 2003 . 14527417 . 10.1016/j.molcel.2003.08.008 . free .
• Perissi V, Aggarwal A, Glass CK, Rose DW, Rosenfeld MG . 18807923 . A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors . Cell . 116 . 4 . 511–26 . February 2004 . 14980219 . 10.1016/S0092-8674(04)00133-3 . free .
• Yoon HG, Choi Y, Cole PA, Wong J . Reading and function of a histone code involved in targeting corepressor complexes for repression . Molecular and Cellular Biology . 25 . 1 . 324–35 . January 2005 . 15601853 . 538779 . 10.1128/MCB.25.1.324-335.2005 .
• Zhang XM, Chang Q, Zeng L, Gu J, Brown S, Basch RS . TBLR1 regulates the expression of nuclear hormone receptor co-repressors . BMC Cell Biology . 7 . 31 . August 2006 . 16893456 . 1555579 . 10.1186/1471-2121-7-31 . free .
• Liu Y, Sun W, Zhang K, Zheng H, Ma Y, Lin D, Zhang X, Feng L, Lei W, Zhang Z, Guo S, Han N, Tong W, Feng X, Gao Y, Cheng S . 6 . Identification of genes differentially expressed in human primary lung squamous cell carcinoma . Lung Cancer . 56 . 3 . 307–17 . June 2007 . 17316888 . 10.1016/j.lungcan.2007.01.016 .

Notes and References

1. Zhang X, Dormady SP, Basch RS . Identification of four human cDNAs that are differentially expressed by early hematopoietic progenitors . Experimental Hematology . 28 . 11 . 1286–96 . November 2000 . 11063877 . 10.1016/S0301-472X(00)00539-7 . free .
2. Zhang J, Kalkum M, Chait BT, Roeder RG . The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2 . Molecular Cell . 9 . 3 . 611–23 . March 2002 . 11931768 . 10.1016/S1097-2765(02)00468-9 . free .
3. Web site: Entrez Gene: TBL1XR1 transducin (beta)-like 1X-linked receptor 1.
4. Web site: OMIM Entry - # 602342 - PIERPONT SYNDROME; PRPTS. www.omim.org. 2020-04-05.
5. Hunter Z, Tsakmaklis N, Demos M, Kofides A, Xu L, Chan G, Chen J, Munsh M, Liu X, Gustine J, Patterson C . 6 . The Genomic Landscape of MYD88 Wild-Type Waldenström's Macroglobulinemia is Characterized by Somatic Mutations in TBL1XR1, the CBM Complex, and NFKB2. . Blood . 2017 . 130 . Supplement 1 . 130 . 10.1182/blood.V130.Suppl_1.4011.4011 . 251168679 .
6. Simpson BS, Camacho N, Luxton HJ, Pye H, Finn R, Heavey S, Pitt J, Moore CM, Whitaker HC . 6 . Genetic alterations in the 3q26.31-32 locus confer an aggressive prostate cancer phenotype . Communications Biology . 3 . 1 . 440 . August 2020 . 32796921 . 10.1038/s42003-020-01175-x . 7429505 . free .
7. Fields AP, Justilien V, Murray NR . The chromosome 3q26 OncCassette: A multigenic driver of human cancer . Advances in Biological Regulation . 60 . 47–63 . January 2016 . 26754874 . 4729592 . 10.1016/j.jbior.2015.10.009 .
8. Daniels G, Li Y, Gellert LL, Zhou A, Melamed J, Wu X, Zhang X, Zhang D, Meruelo D, Logan SK, Basch R, Lee P . 6 . TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth . Endocrine-Related Cancer . 21 . 1 . 127–42 . February 2014 . 24243687 . 3947037 . 10.1530/ERC-13-0293 .
9. Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J . N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso . Molecular Cell . 12 . 3 . 723–34 . September 2003 . 14527417 . 10.1016/j.molcel.2003.08.008 . free .
10. Yoon HG, Chan DW, Huang ZQ, Li J, Fondell JD, Qin J, Wong J . Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1 . The EMBO Journal . 22 . 6 . 1336–46 . March 2003 . 12628926 . 151047 . 10.1093/emboj/cdg120 .