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Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation.

ABSTRACT: Nucleophosmin (NPM) is an important nucleolar phosphoprotein with pleiotropic functions in various cellular processes. In this study, we have further examined the largely uncharacterized role of NPM in transcriptional regulation by uncovering novel NPM-binding transcriptional factors. Among potential interactors, we found that activating protein transcription factor 2 (AP2)alpha forms a complex with NPM during retinoic-acid-induced cell differentiation. We show that this complex is recruited to the promoters of certain retinoic-acid-responsive genes, including NPM itself. Such binding of AP2alpha, and consequent recruitment of NPM, is selective and dependent on a consensus AP2alpha-binding sequence. Remarkably, suppression of NPM by RNA interference alleviates the repression of gene expression mediated by retinoic acid and AP2alpha. Our findings further show that, on promoter binding, NPM probably exerts its repressive effect by inducing a change in local chromatin structure that also engages histone deacetylases. This study unveils a hitherto unrecognized transcriptional corepressor function of the NPM protein, and highlights a novel mechanism by which NPM regulates cell growth and differentiation.

SUBMITTER: Liu H

PROVIDER: S-EPMC1852768 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation.

Liu Hsuan H Tan Bertrand Chin-Ming BC Tseng Kai Hung KH Chuang Ching Ping CP Yeh Chun-Wei CW Chen Kwang-Den KD Lee Sheng-Chung SC Yung Benjamin Yat-Ming BY

EMBO reports 20070223 4

Nucleophosmin (NPM) is an important nucleolar phosphoprotein with pleiotropic functions in various cellular processes. In this study, we have further examined the largely uncharacterized role of NPM in transcriptional regulation by uncovering novel NPM-binding transcriptional factors. Among potential interactors, we found that activating protein transcription factor 2 (AP2)alpha forms a complex with NPM during retinoic-acid-induced cell differentiation. We show that this complex is recruited to ...[more]

PMID: 17318229

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Project description: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.

Dataset Information

Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation.

Publications

Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation.

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