Upregulation of ATBF1 by progesterone-PR signaling and its functional implication in mammary epithelial cells

Li, Mei; Zhao, Dan; Ma, Guansheng; Zhang, Baotong; Fu, Xiaoying; Zhu, Zhengmao; Fu, Liwei; Sun, Xiaodong; Dong, Jin‐Tang

doi:10.1016/j.bbrc.2012.11.009

Cited by 26 publications

(18 citation statements)

References 34 publications

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“…As a transcription factor, ATBF1 is expected to be located in the nucleus to function, and its nuclear localization has been confirmed in both cultured cells and human tissues [3], [10], [41]. It has also been demonstrated that in the nucleus, ATBF1 interacts with other nuclear factors to regulate gene expression and cell proliferation [21], [42].…”

Section: Discussionmentioning

confidence: 95%

Characterization of Nuclear Localization and SUMOylation of the ATBF1 Transcription Factor in Epithelial Cells

Sun

Dong

et al. 2014

PLoS ONE

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ATBF1/ZFHX3 is a large transcription factor that functions in development, tumorigenesis and other biological processes. ATBF1 is normally localized in the nucleus, but is often mislocalized in the cytoplasm in cancer cells. The mechanism underlying the mislocalization of ATBF1 is unknown. In this study, we analyzed the nuclear localization of ATBF1, and found that ectopically expressed ATBF1 formed nuclear body (NB)-like dots in the nucleus, some of which indeed physically associated with promyelocytic leukemia (PML) NBs. We also defined a 3-amino acid motif, KRK2615-2617, as the nuclear localization signal (NLS) for ATBF1. Interestingly, diffusely distributed nuclear SUMO1 proteins were sequestered into ATBF1 dots, which could be related to ATBF1's physical association with PML NBs, known SUMOylation hotspots. Furthermore, ATBF1 itself was SUMOylated. ATBF1 SUMOylation occurred at more than 3 lysine residues including K2349, K2806 and K3258 and was nuclear specific. Finally, the PIAS3 SUMO1 E3 ligase, which interacts with ATBF1 directly, diminished rather than enhanced ATBF1 SUMOylation, preventing the co-localization of ATBF1 with SUMO1 in the nucleus. These findings suggest that nuclear localization and SUMOylation are important for the transcription factor function of ATBF1, and that ATBF1 could cooperate with PML NBs to regulate protein SUMOylation in different biological processes.

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Section: Discussionmentioning

confidence: 95%

Characterization of Nuclear Localization and SUMOylation of the ATBF1 Transcription Factor in Epithelial Cells

Sun

Dong

et al. 2014

PLoS ONE

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“…In addition, ATBF1 was observed to translocate to the nucleus by forming a complex with runt domain transcription factor 3 (RUNX3), in response to transforming growth factor (TGF)-β signal transduction (9). Previous studies have demonstrated that the subcellular localization of ATBF1 may be a potential prognostic maker for skin cancer and head and neck cancer (10,11). However, information regarding the post-transcriptional modifications of the ATBF1 protein and their association with the nuclear translocation of ATBF1 remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Expression and subcellular localization of AT motif binding factor 1 in colon tumours

Kataoka

Miura

Kikuchi³

et al. 2017

Molecular Medicine Reports

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AT motif binding factor 1 (ATBF1) is a transcriptional regulator that functions as a tumour suppressor to negatively affect cancer cell growth. In the present study four specific polyclonal antibodies against ATBF1 were generated, and the expression and intracellular localization of ATBF1 in colonic mucosae, polyps, adenoma and adenocarcinoma tissue samples were investigated. The four polyclonal antibodies produced were as follows: MB34 and MB49, which recognize the N- and C-terminal fragments of ATBF1, respectively; and D1-120 and MB44, which recognize the middle fragments of ATBF1 that contain three nuclear localization signals (NLS). In total, 191 colon samples were examined by immunohistochemical analysis. In addition, colon cancer cells were transfected with four ATBF1 expression vectors, and the subcellular localization of each fragment was examined. Normal colon mucosal cells were not observed to express ATBF1. However, a small number of hyperplastic polyps, serrated adenomas and tubular adenomas expressed ATBF1. Colon cancer cells were observed to express D1-120- and MB44-reactive middle fragments of ATBF1 in their cell nuclei. However, the N- and C-terminal fragments of ATBF1 did not translocate to the nucleus. Transfection of ATBF1 fragments revealed cleavage of the ATBF1 protein and nuclear translocation of the cleaved middle portion containing the NLS. A positive correlation between the cytoplasmic localization of the N- and C-termini of ATBF1, nuclear localization of the middle portion of ATBF1 and malignant cancer cell invasion was observed. In conclusion, the results of the present study suggest that alterations in the expression and subcellular localization of ATBF1, as a result of post-transcriptional modifications, are associated with malignant features of colon tumours.

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“…In mouse mammary glands, we previously demonstrated that Zfhx3 mRNA expression varies at different stages during development, reaching the highest level at lactation (20), and that Zfhx3 regulates pubertal mammary gland development (20). In addition, both estrogen and progesterone, two hormones essential for normal mammary gland development, induce or enhance the transcription of ZFHX3 in human and mouse mammary epithelial cells (21,22), although estrogen also causes protein degradation of ZFHX3 when too much estrogen is present (21). Taken together with the observation that deletion of Zfhx3 in mouse prostates alters the transcription level of Prlr (17), a key regulator of lactogenic differentiation in the mammary gland, we hypothesize that ZFHX3 is more relevant to lactogenic differentiation during mammary gland development.…”

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confidence: 99%

Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity

Zhao

Zhang

et al. 2016

Journal of Biological Chemistry

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The zinc finger homeobox 3 (ZFHX3, also named ATBF1 for AT motif binding factor 1) is a transcription factor that suppresses prostatic carcinogenesis and induces neuronal differentiation. It also interacts with estrogen receptor ␣ to inhibit cell proliferation and regulate pubertal mammary gland development in mice. In the present study, we examined whether and how Zfhx3 regulates lactogenic differentiation in mouse mammary glands. At different stages of mammary gland development, Zfhx3 protein was expressed at varying levels, with the highest level at lactation. In the HC11 mouse mammary epithelial cell line, an in vitro model of lactogenesis, knockdown of Zfhx3 attenuated prolactin-induced ␤-casein expression and morphological changes, indicators of lactogenic differentiation. In mouse mammary tissue, knock-out of Zfhx3 interrupted lactogenesis, resulting in underdeveloped glands with much smaller and fewer alveoli, reduced ␤-casein expression, accumulation of large cytoplasmic lipid droplets in luminal cells after parturition, and failure in lactation. Mechanistically, Zfhx3 maintained the expression of Prlr (prolactin receptor) and Prlr-Jak2-Stat5 signaling activity, whereas knockdown and knock-out of Zfhx3 in HC11 cells and mammary tissues, respectively, decreased Prlr expression, Stat5 phosphorylation, and the expression of Prlr-Jak2-Stat5 target genes. These findings indicate that Zfhx3 plays an essential role in proper lactogenic development in mammary glands, at least in part by maintaining Prlr expression and Prlr-Jak2-Stat5 signaling activity.

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Upregulation of ATBF1 by progesterone-PR signaling and its functional implication in mammary epithelial cells

Cited by 26 publications

References 34 publications

Characterization of Nuclear Localization and SUMOylation of the ATBF1 Transcription Factor in Epithelial Cells

Characterization of Nuclear Localization and SUMOylation of the ATBF1 Transcription Factor in Epithelial Cells

Expression and subcellular localization of AT motif binding factor 1 in colon tumours

Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity

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