The levels of RAC3 expression are up regulated by TNF in the inflammatory response

Alvarado, Cecilia Viviana; Rubio, Miguel; Larrosa, Pablo Nicolás Fernández; Panelo, Laura Carolina; Azurmendi, Pablo Javier; Grecco, Marina Ruiz; Martínez-Nöel, Giselle Astrid; Costas, Mónica Alejandra

doi:10.1016/j.fob.2014.04.009

Cited by 15 publications

(27 citation statements)

References 41 publications

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“…RAC3 is a known high expression molecule in several types of tumors including colorectal cancer [ 29 ]. However, it was not clearly determined at present if this overexpression could be early detected at tumor initiation and then homogeneously sustained along the cancer progression.…”

Section: Resultsmentioning

confidence: 99%

“…In this regard, inflammation is increasingly recognized as a critical component in tumor initiation and progression [ 41 , 42 ]. Furthermore, we have previously demonstrated that inflammatory cytokines as TNF may upregulate the RAC3 gene expression [ 29 ]. Therefore, in this context, the induction of malignant or premalignant lesions from cells acquiring this RAC3 overexpression and possible additional mutations or epygenomic rearrangements sounds as a possible source for tumor initiating cells.…”

Section: Discussionmentioning

confidence: 99%

“…In normal healthy tissues RAC3 expression is downregulated in mature and differentiated cells, as well as in aged tissues [ 20 ], suggesting that changes in their levels may be playing a critical role in development. However, we have previously found that inflammatory cytokines like TNF up-regulate the expression of this oncogene [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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High RAC3 expression levels are required for induction and maintaining of cancer cell stemness

et al. 2017

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RAC3 is a transcription coactivator, usually overexpressed in several tumors and required to maintain the pluripotency in normal stem cells.In this work we studied the association between RAC3 overexpression on cancer cell stemness and the capacity of this protein to induce cancer stem properties in non tumoral cells.We performed in vitro and in vivo experiments using two strategies: by overexpressing RAC3 in the non tumoral cell line HEK293 and by silencing RAC3 in the human colorectal epithelial cell line HCT116 by transfection. Furthermore, we analysed public repository microarrays data from human colorectal tumors in different developmental stages. We found that RAC3 overexpression was mainly associated to CD133+ side-population of colon cancer cells and also to early and advanced stages of colon cancer, involving increased expression of mesenchymal and stem markers. In turn, RAC3 silencing induced diminished tumoral properties and cancer stem cells as determined by Hoechst efflux, tumorspheres and clonogenic growth, which correlated with decreased Nanog and OCT4 expression. In non tumoral cells, RAC3 overexpression induced tumoral transformation; mesenchymal phenotype and stem markers expression. Moreover, these transformed cells generated tumors in vivo.Our results demonstrate that RAC3 is required for maintaining and induction of cancer cell stemness.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High RAC3 expression levels are required for induction and maintaining of cancer cell stemness

et al. 2017

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“…The corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) preferentially interacts with the antagonist-bound PRA, and the coactivators steroid receptor coactivator 1 (SRC-1) and 2 (SRC-2) have a higher affinity for PRB. 9 Less information is available regarding SRC-3 (AIB1), an oncogene associated with endocrine resistance [10][11][12][13] and PR action in the mammary gland. 14 Antiprogestins inhibit breast cancer growth in several experimental models [reviewed in Ref.…”

mentioning

confidence: 99%

Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio viaAIB1 or SMRT recruitment to the CCND1 and MYC promoters

Wargon

Riggio

Giulianelli

et al. 2014

Intl Journal of Cancer

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There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.

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“…With the MR model it has been shown that the whole undissociated complex is detectable in the nucleus for several minutes after translocation (Galigniana et al 2010b; Grossmann et al 2012). One other protein that can be associated with the nuclear translocation complex is RAC3 (receptor-associated co-activator 3), a protein that exerts an anti-apoptotic activity by activating NF-kappaB, AKT and p38 MAPK and by inhibition of caspase 9, AIF (apoptosis-inducing factor) and ERK2 (extracellular signal regulated kinase 3/MAPK6) (Colo et al 2008; Alvarado et al 2014). …”

Section: Inductors Of Hsp90(ab1)mentioning

confidence: 99%

HSP90AB1: Helping the good and the bad

Haase

Fitze

2016

Gene

111

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HSP90AB1 (heat shock protein 90 kDA alpha, class B, member 1), also known as HSP90beta, is a member of the large family of HSPs which function as molecular chaperones. Chaperones, by binding to client proteins, support proper protein folding and maintain protein stability, especially after exposure to various kinds of cellular stress. Client proteins belong to various protein families including kinases, ubiquitin ligases and transcription factors. HSP90 proteins act as dimers and bind clients with the help of co-chaperones. The cochaperones influence many functions including client binding, ATPase activity or ATP binding of HSP90. HSPs are necessary for a large scale of cellular processes and therefore essential for cell survival. Since client proteins can be mutant proteins that would be degraded without the help of chaperones, HSPs also promote tumor formation and cancer cell proliferation. As such, they are also targets for new therapeutic approaches in cancer treatment. This review focuses on recent studies on HSP90AB1, if possible in comparison with its close homologue HSP90AA1.

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The levels of RAC3 expression are up regulated by TNF in the inflammatory response

Cited by 15 publications

References 41 publications

High RAC3 expression levels are required for induction and maintaining of cancer cell stemness

High RAC3 expression levels are required for induction and maintaining of cancer cell stemness

Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio viaAIB1 or SMRT recruitment to the CCND1 and MYC promoters

HSP90AB1: Helping the good and the bad

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