Developmental transcriptional regulation by SUMOylation, an evolving field

Monribot‐Villanueva, Juan L.; Zurita, Mario; Vázquez, Martha

doi:10.1002/dvg.23009

Cited by 9 publications

(8 citation statements)

References 123 publications

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“…Indeed, the covalent attachment of SUMO modifiers essentially affects the intramolecular and intermolecular interactions of substrate proteins, thereby altering their activity, subcellular localization, or stability. Functionally, SUMOylation plays a paramount role in the regulation of gene transcription, since most of its targets are transcription factors, transcriptional co-regulators, chromatin-remodeling proteins, and DNA repair enzymes 104 . As the expression of SUMO-conjugating enzymes is frequently deregulated in cancer 105 , and several EMT-inducing transcription factors are well-known targets of the SUMOylation machinery 106 , it is tempting to speculate that SUMOylation may be a driving force behind the plasticity of invasive carcinoma cells.…”

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 99%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 99%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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“…If TnaA is influencing BRAHMA BAP complex function, it may act close to the promoter or on regulatory elements such as enhancers where BAP complexes are remodeling chromatin. TnaA may also have other targets than the BAP complex and have a wider target specificity as has been shown for other E3 SUMO ligases (reviewed in [ 8 ]). These are questions still unanswered and for example, chromatin immunoprecipitation experiments with TnaA antibodies that recognize specific isoforms at different times of development, will be helpful to start to determine the range of action of these TrxG proteins.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, there are several types of E3 ligases that choose or help the SUMOylation of a target protein. SUMOylation of a target protein can change its sub-compartmentalization within the cell or nucleus, can favor a change of partners and/or it can label it for degradation (revised in [ 8 ]). The PIAS (Protein Inhibitors of Acivated STAT [Signal Transducers and Activators of Transcription]) family is a subgroup of E3 SUMO ligases that interact physically with E2 enzymes through a canonical 42 amino-acidic residues SP-RING (Siz/PIAS-Really Interesting) zinc finger [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

The role of the trithorax group TnaA isoforms in Hox gene expression, and in Drosophila late development

Rosales-Vega¹,

Hernández-Becerril²,

Murillo‐Maldonado³

et al. 2018

PLoS ONE

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Regulation of developmental gene expression in eukaryotes involves several levels. One of them is the maintenance of gene expression along the life of the animal once it is started by different triggers early in development. One of the questions in the field is when in developmental time, the animal start to use the different maintenance mechanisms. The trithorax group (TrxG) of genes was first characterized as essential for maintaining homeotic gene expression. The TrxG gene tonalli interacts genetically and physically with genes and subunits of the BRAHMA BAP chromatin remodeling complex and encodes TnaA proteins with putative E3 SUMO-ligase activity. In contrast to the phenocritic lethal phase of animals with mutations in other TrxG genes, tna mutant individuals die late in development. In this study we determined the requirements of TnaA for survival at pupal and adult stages, in different tna mutant genotypes where we corroborate the lack of TnaA proteins, and the presence of adult homeotic loss-of-function phenotypes. We also investigated whether the absence of TnaA in haltere and leg larval imaginal discs affects the presence of the homeotic proteins Ultrabithorax and Sex combs reduced respectively by using some of the characterized genotypes and more finely by generating TnaA defective clones induced at different stages of development. We found that, tna is not required for growth or survival of imaginal disc cells and that it is a fine modulator of homeotic gene expression.

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“…Functions of proteins can be achieved by post-translational modification, for example with small ubiquitin-related modifier (SUMO) [ 35 , 36 ]. We previously demonstrated that the function of Prox1 as a co-repressor might be inhibited by sumoylation [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Prox1 represses IL-2 gene expression by interacting with NFAT2

Zhang

Wang

et al. 2017

Oncotarget

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Interleukin-2 (IL-2) is critical for T lymphocyte activation and regulated by many transcriptional factors. Prospero-related homeobox 1 (Prox1) is a multifunctional transcription factor, which can work as either a transcriptional activator or repressor depending on the cellular and developmental environment. We previously reported the Prox1 expression in T cells, raising the possibility of Prox1 involvement in the regulation of T cell function and IL-2 production. Here we demonstrated that the Prox1 expression in CD4+ T cells was downregulated by T cell receptor (TCR) activation. Overexpression of Prox1 attenuated IL-2 production, while knockdown of endogenous Prox1 by small interfering RNA increased IL-2 expression. Mechanistically, we showed that Prox1 inhibited the IL-2 promoter activity, and associated with the minimal IL-2 promoter. Prox1 repressed the nuclear factor of activated T cells 2 (NFAT2)-dependent transactivation of IL-2 gene by physically binding to NFAT2. The N-terminal region of Prox1 was essential for the binding and repression. In summary, our findings established Prox1 as a negative regulator in IL-2 gene expression through the direct interaction with NFAT2.

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Developmental transcriptional regulation by SUMOylation, an evolving field

Cited by 9 publications

References 123 publications

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

The role of the trithorax group TnaA isoforms in Hox gene expression, and in Drosophila late development

Prox1 represses IL-2 gene expression by interacting with NFAT2

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