ROCK and Nuclear Factor-κB–dependent Activation of  Cyclooxygenase-2 by Rho GTPases: Effects on Tumor Growth and Therapeutic  Consequences

Benitah, Salvador Aznar; Valerón, Pilar F.; Lacal, Juan Carlos

doi:10.1091/mbc.e03-01-0016

Cited by 75 publications

(72 citation statements)

References 51 publications

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“…4F) abrogated LGR5-induced reporter activity. It has been suggested that NF-κB is a link between inflammation and tumor development induced by the Rho signaling pathway (Benitah et al, 2003;Karin et al, 2002;Lin and Karin, 2003;Segain et al, 2003). In addition, NF-κB plays a role in the regulation of stem cell self-renewal and differentiation (Schugar et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

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Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach.LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα 12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G 12/13 signaling.

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Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

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“…This 4HT-ROCK er -mediated NF-κβ expression is consistent with activation of NF-κβ by Rho-induced, nuclear translocation of p65/RelA; independent of Ras GTPases. 9,10 Whether this is exerting a protective or oncogenic role in this context is unclear, 25 but elevated NF-κβ inflammatory roles would be consistent with wound promotion, currently associated with fos/Jun/AP1 activation; 45 hence whether fos/AP1 promotes via deregulation of NF-κβ is under investigation.…”

Section: Discussionmentioning

confidence: 99%

ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

et al. 2016

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ROCK2/rasHa cooperation induce malignant conversion via p53 loss, elevated NF-κβ and tenascin C-associated rigidity but p21 inhibits ROCK2/NF-κβ-mediated progression. Oncogene, 36, pp. 2529Oncogene, 36, pp. -2542Oncogene, 36, pp. . (doi:10.1038Oncogene, 36, pp. /onc.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/129163/ Malignancy depended on ROCK er /p-Mypt1 expression, as cessation of 4HT-treatment induced disorganised tissue architecture and p21-associated differentiation in wdSCCs; yet tenascin C retention in connective tissue ECM suggests the rigidity laid down for conversion persists. Novel papilloma outgrowths appeared expressing intense, basal-layer p21 which confined endogenous ROCK2/p-Mypt1/NF-κβ to supra-basal layers, and was paralleled by restored basal-layer p53. In later SCCs, 4HT-cessation became irrelevant as endogenous ROCK2 expression increased, driving progression via p21 loss, elevated NF-κβ expression and tenascin C-associated rigidity; with p-Mypt1 inactivation/actinomyosin-mediated contractility to facilitate invasion. However, p21-associated inhibition of early-stage malignant progression and the intense expression in papilloma outgrowths, identifies a novel, significant antagonism between p21 and ras Ha /ROCK2/NF-κβ signalling in skin 3 carcinogenesis. Collectively these data show that ROCK2 activation induces malignancy in ras Ha -initiated/promoted papillomas in the context of p53 loss and novel NF-κβ expression; whilst increased tissue rigidity and cell motility/contractility help mediate tumour progression.4

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“…Previous studies have shown, that the MAPK pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in IBC (Van Golen et al, 2002). Other studies have shown that the stimulatory effect of the RhoC GTPaseactivity on tumour growth depends on NF-kB activity (Benitah et al, 2003). One of the first molecular alterations characterised in IBC was the overexpression of RhoC (Van Golen et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

NF-κB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation

et al. 2007

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Activation of NF-kB in inflammatory breast cancer (IBC) is associated with loss of estrogen receptor (ER) expression, indicating a potential crosstalk between NF-kB and ER. In this study, we examined the activation of NF-kB in IBC and non-IBC with respect to ER and EGFR and/or ErbB2 expression and MAPK hyperactivation. A qRT -PCR based ER signature was evaluated in tumours with and without transcriptionally active NF-kB, as well as correlated with the expression of eight NF-kB target genes. Using a combined ER/ NF-kB signature, hierarchical clustering was executed. Hyperactivation of MAPK was investigated using a recently described MAPK signature (Creighton et al, 2006), and was linked to tumour phenotype, ER and EGFR and/or ErbB2 overexpression. The expression of most ER-modulated genes was significantly elevated in breast tumours without transcriptionally active NF-kB. In addition, the expression of most ER-modulated genes was significantly anticorrelated with the expression of most NF-kB target genes, indicating an inverse correlation between ER and NF-kB activation. Clustering using the combined ER and NF-kB signature revealed one cluster mainly characterised by low NF-kB target gene expression and a second one with elevated NF-kB target gene expression. The first cluster was mainly characterised by non-IBC specimens and IHC ER þ breast tumours (13 out of 18 and 15 out of 18 respectively), whereas the second cluster was mainly characterised by IBC specimens and IHC ERÀ breast tumours (12 out of 19 and 15 out of 19 respectively) (Pearson w 2 , Po0.0001 and Po0.0001 respectively). Hyperactivation of MAPK was associated with both ER status and tumour phenotype by unsupervised hierarchical clustering using the MAPK signature and was significantly reflected by overexpression of EGFR and/or ErbB2. NF-kB activation is linked to loss of ER expression and activation in IBC and in breast cancer in general. The inverse correlation between NF-kB activation and ER activation is due to EGFR and/or ErbB2 overexpression, resulting in NF-kB activation and ER downregulation.

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ROCK and Nuclear Factor-κB–dependent Activation of Cyclooxygenase-2 by Rho GTPases: Effects on Tumor Growth and Therapeutic Consequences

Cited by 75 publications

References 51 publications

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

NF-κB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation

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