Kaiso Directs the Transcriptional Corepressor MTG16 to the Kaiso Binding Site in Target Promoters
Year: 2012
Type: article
Abstract: Myeloid translocation genes (MTGs) are transcriptional corepressors originally identified in acute myelogenous leukemia that have recently been linked to epithelial malignancy with non-synonymous mutations identified in both MTG8 and MTG16 in colon, breast, and lung carcinoma in addition to functioning as negative regulators of WNT and Notch signaling. A yeast two-hybrid approach was used to discover novel MTG binding partners. This screen identified the Zinc fingers, C2H2 and BTB domain containing (ZBTB) family members ZBTB4 and ZBTB38 as MTG16 interacting proteins. ZBTB4 is downregulated in breast cancer and modulates p53 responses. Because ZBTB33 (Kaiso), like MTG16, modulates Wnt signaling at the level of TCF4, and its deletion suppresses intestinal tumorigenesis in the Apc(Min) mouse, we determined that Kaiso also interacted with MTG16 to modulate transcription. The zinc finger domains of Kaiso as well as ZBTB4 and ZBTB38 bound MTG16 and the association with Kaiso was confirmed using co-immunoprecipitation. MTG family members were required to efficiently repress both a heterologous reporter construct containing Kaiso binding sites (4×KBS) and the known Kaiso target, Matrix metalloproteinase-7 (MMP-7/Matrilysin). Moreover, chromatin immunoprecipitation studies placed MTG16 in a complex occupying the Kaiso binding site on the MMP-7 promoter. The presence of MTG16 in this complex, and its contributions to transcriptional repression both required Kaiso binding to its binding site on DNA, establishing MTG16-Kaiso binding as functionally relevant in Kaiso-dependent transcriptional repression. Examination of a large multi-stage CRC expression array dataset revealed patterns of Kaiso, MTG16, and MMP-7 expression supporting the hypothesis that loss of either Kaiso or MTG16 can de-regulate a target promoter such as that of MMP-7. These findings provide new insights into the mechanisms of transcriptional control by ZBTB family members and broaden the scope of co-repressor functions for the MTG family, suggesting coordinate regulation of transcription by Kaiso/MTG complexes in cancer.
Source: PLoS ONE
Authors: Caitlyn W. Barrett, J. Joshua Smith, Lauren C. Lu, Nicholas Markham, Kristy R. Stengel, Sarah P. Short, Baolin Zhang, Aubrey A. Hunt, Barbara M. Fingleton, Robert H. Carnahan, Michael E. Engel, Xi Chen, R. Daniel Beauchamp, Keith T. Wilson, Scott W. Hiebert, Albert B. Reynolds, Christopher S. Williams
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: American Cancer Society, U.S. Department of Veterans Affairs, Vanderbilt University, Vanderbilt University Medical Center, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, National Center for Complementary and Integrative Health
Awards: Regulation of MTG16 and Notch signaling in hematopoiesis, G1161937598, G1182793083, G1331566780, G1339403715, The role of MTGR1 in intestinal biology and inflammation, G1942042315, G2265622010, G2308744219, G256475304, G2659027680, G332351177, Immunomodulatory effects of arginine supplementation in colitis and colon cancer, G3549828030, G3619590958, G3724712001, G4107354744, G4290769314, G4308745201, G4335719375, G4353979765, G437908500, G4425699080, G4694584828, G560889077, G563474107, G5679716143, G5868276417, G6070163016, G6263508347, G627390404, G6678749481, G725763919, G7406452918, G7653134492, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G780788820, G9000001553, G9000033427, G9000043901, G9000064184, G9000282695, G9000300101, Molecular and Cellular Basis for Digestive Diseases, G932275120, G949362299, G959610197
OpenAlex ID: W2075706189