Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis

Bagheri‐Yarmand, Rozita; Talukder, Amjad H.; Wang, Rui An; Vadlamudi, Ratna K.; Kumar, Rakesh

doi:10.1242/dev.01213

Cited by 86 publications

(29 citation statements)

References 45 publications

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“…Further- more, MTA3-induced hypobranching in the mammary gland is mechanistically linked with the direct corepressor activity of the MTA3-HDAC complex on Wnt4 chromatin. These effects of MTA3 are opposite those of MTA1 in virgin mammary gland (41). These findings support the notion of physiological differences among the MTA family members and underscore the lack of functional redundancy among individual MTA proteins.…”

Section: Mta1 In Mouse Mammarysupporting

confidence: 77%

“…Gland Development-A recent study showed that forced overexpression of MTA1 in the mouse mammary gland epithelium was accompanied by extensive ductal branching and proliferation in virgin glands, which was mechanistically linked to an altered ratio of progesterone receptor A and B isoforms (41). These data suggest a role for MTA1 in mammary gland development.…”

Section: Mta1 In Mouse Mammarymentioning

confidence: 98%

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Metastasis Tumor Antigens, an Emerging Family of Multifaceted Master Coregulators

Manavathi

Kumar

2007

Journal of Biological Chemistry

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127

149

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Regulation of fundamental genetic processes demands dynamic participation of transcription factors, their coregulators, and multiprotein chromatin remodeling activities at target genes. One family of chromatin modifiers that is ubiquitously expressed is the metastasis tumor antigens (MTA), which are integral parts of nucleosome remodeling and histone deacetylation (NuRD) complexes. MTA family members exist in distinct NuRD complexes, and functional redundancy is lacking among MTA family members. MTA proteins regulate divergent cellular pathways, including hormonal action, epithelial-to-mesenchymal transitions, differentiation, protein stability and development, and cell fate programs by modifying the acetylation status of crucial target genes. Intriguingly, at least one member of this family, MTA1, itself undergoes acetylation and acts as a coactivator in certain contexts. We discuss the roles of the MTA family of chromatin modifiers, with an emphasis on their physiologic functions.Dynamic alterations in chromatin structure facilitate or repress access of transcription complexes to target DNAs, leading to transcriptional changes and the regulation of functions associated with the gene products (1). These complexes modify DNA accessibility for cofactors by affecting DNA-histone interactions, nucleosome sliding, or relocation. In addition, the transcriptional state is influenced by covalent modification of the core histones (2). Among histone modifications, acetylation plays a pivotal role in chromatin remodeling (3). Core histones are subject to reversible acetylation at select lysine residues in their N-terminal domains through the coordinate activity of histone acetyltransferases and histone deacetylases (HDACs) 2 (3). Histone acetylation correlates with transcriptional activity, whereas deacetylation favors transcriptional repression. The mechanism of action of histone acetyltransferases is extensively reviewed elsewhere in the literature (4). Here we discuss the current understanding of the MTA family of coregulators, which are essential components of HDAC-containing NuRD transcriptional complexes. NuRD Complex, a Dynamic Switch for Histone Deacetylation and Chromatin RemodelingDeacetylation of histones via HDACs is carried out by two major complexes, Sin3 and NuRD (5, 6). The Sin3 complex contains seven polypeptides: HDAC1, HDAC2, RbAp46, RbAp48, Sin3, SAP18, and SAP30. This complex participates in nuclear hormone receptor repression of target genes (5, 7). NuRD complexes share four core proteins (HDAC1, HDAC2, RbAp46, and RbAp48) with the Sin3 complex and contain Mi-2␣/␤, MTA1/2, and p66 (5). In the NuRD complex, HDAC1/2 participate in the deacetylation process; Mi-2␣/␤ proteins with a chromodomain exhibit a DNA helicase/ATPase activity; and RbAp46/48 participate in histone binding. The roles of p66␣/␤ in NuRD complex are complex as p66 proteins are sumoylated, and SUMO-modified p66␣ efficiently interacts with HDAC1, whereas RbAp46 binds to SUMO-modified p66␤ (8, 9). All three MTA family proteins are found ...

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Section: Mta1 In Mouse Mammarysupporting

confidence: 77%

Section: Mta1 In Mouse Mammarymentioning

confidence: 98%

Metastasis Tumor Antigens, an Emerging Family of Multifaceted Master Coregulators

Manavathi

Kumar

2007

Journal of Biological Chemistry

Self Cite

127

149

View full text Add to dashboard Cite

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“…These mice also developed hyperplastic nodules and mammary tumors [40]. In this study, the underlying molecular mechanisms were also examined, and the results suggested that MTA1 dysregulation in mammary epithelium and cancer cells triggered down-regulation of the progesterone receptor-B isoform and up-regulation of the progesterone receptor-A isoform, resulting in the up-regulation of the progesterone receptor-A target genes Bcl-XL and cyclin D1 in mammary glands of virgin mice.…”

Section: Other Possible Functions Of Mta Proteins In Cancermentioning

confidence: 75%

“…This property is in contrast to MTA1-transgenic mice, where the inappropriate development of mammary glands results in the development of hyperplastic nodules and mammary tumors, including adenocarcinomas and lymphomas [8,40]. MTA3 also represses Wnt4 transcription and Wnt4 secretion, inhibiting Wnt-target genes in mammary epithelial cells.…”

Section: Repression Of the Transactivating Function Of Era By Mta Promentioning

confidence: 89%

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The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications

Toh

Nicolson

2008

Clin Exp Metastasis

193

191

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MTA (metastasis-associated gene) is a newly discovered family of cancer progression-related genes and their encoded products. MTA1, the first gene found in this family, has been repeatedly reported to be overexpressed along with its protein product MTA1 in a wide range of human cancers. In addition, the expression of MTA1/MTA1 correlates with the clinicopathological properties (malignant properties) of human cancers. MTA proteins are transcriptional co-repressors that function in histone deacetylation and are involved in the NuRD complex, which contains nucleosome remodeling and histone deacetylating molecules. MTA1 expression correlates with tumor formation in the mammary gland. In addition, MTA1 converts breast cancer cells to a more aggressive phenotype by repression of the estrogen receptor (ER) alpha trans-activation function through deacetylation of the chromatin in the ER-responsive element of ER-responsive genes. Furthermore, MTA1 plays an essential role in c-MYC-mediated cell transformation. Another member of this family, MTA3, is induced by estrogen and represses the expression of the transcriptional repressor Snail, a master regulator of "epithelial to mesenchymal transitions", resulting in the expression of the cell adhesion molecule E-cadherin and maintenance of a differentiated, normal epithelial phenotype in breast cells. In addition, tumor suppressor p53 protein is deacetylated and inactivated by both MTA1 and MTA2, leading to inhibition of growth arrest and apoptosis. Moreover, a hypoxia-inducible factor-1alpha (HIF-1alpha) is also deacetylated and stabilized by MTA1, resulting in angiogenesis. Thus, MTA proteins, especially MTA1, represent a possible set of master co-regulatory molecules involved in the carcinogenesis and progression of various malignant tumors. MTA proteins are proposed to be important new tools for clinical application in cancer diagnosis and treatment.

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Constitutive overexpression of Id‐1 in mammary glands of transgenic mice results in precocious and increased formation of terminal end buds, enhanced alveologenesis, delayed involution

Shin

Jang

Kang

et al. 2011

Journal Cellular Physiology

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Inhibitor of differentiation-1 (Id-1) has been shown to play an essential role in cell proliferation, invasion, migration, and anti-apoptosis. However, the effect of Id-1 in mammary gland development remains unknown. Here, we generated MMTV-Id-1 transgenic mice to study the role of Id-1 in mammary gland development. In virgin mice, Id-1 overexpression led to precocious development and delayed regression of terminal end buds (TEBs) compared with wild-type mice. The number of BrdU-positive cells and the expression of Wnt signaling molecules, β-catenin and cyclin D1, which regulate ductal extension and TEB formation in virgin, were statistically higher in Id-1 transgenic mice than in wild-type mice. Id-1 also had an effect on the formation and proliferation of lobuloalveolar structures during early and mid-pregnancy. Id-1 transgenic mice had more lobulated and prominent alveolar budding than wild-type mice and had significantly greater counts of lobuloalveolar structures in early pregnancy. The expression of BrdU, β-catenin, and cyclin D1 was also predominantly increased in Id-1 transgenic mice. Moreover, Id-1 transgenic mice showed delayed involution. Id-1 regulated the expression levels of anti-apoptotic Bcl-2 and pro-apoptotic Bax, and resulted in delay of apoptotic peak during postlactational involution. We also found that Id-1 was able to modulate expression of the regulators of Wnt/β-catenin signaling such as phospho-Akt, BMP2, FGF3, and RAR-β in tubuloalveolar development of mammary glands. Taken together, our results suggest that Id-1 plays a pivotal role in mammary gland development through Wnt signaling-mediated acceleration of precocity and alveologenesis and Bcl-2 family members-mediated delay of involution.

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Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis

Cited by 86 publications

References 45 publications

Metastasis Tumor Antigens, an Emerging Family of Multifaceted Master Coregulators

Metastasis Tumor Antigens, an Emerging Family of Multifaceted Master Coregulators

The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications

Constitutive overexpression of Id‐1 in mammary glands of transgenic mice results in precocious and increased formation of terminal end buds, enhanced alveologenesis, delayed involution

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