Dataset Information

MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling.

ABSTRACT: MSK (mitogen- and stress-activated protein kinase) 1 and MSK2 are kinases activated downstream of either the ERK (extracellular-signal-regulated kinase) 1/2 or p38 MAPK (mitogen-activated protein kinase) pathways in vivo and are required for the phosphorylation of CREB (cAMP response element-binding protein) and histone H3. Here we show that the MSKs are involved in regulating the transcription of the immediate early gene Nur77. Stimulation of mouse embryonic fibroblasts with PMA, EGF (epidermal growth factor), TNF (tumour necrosis factor) or anisomycin resulted in induction of the Nur77 mRNA. The induction of Nur77 by TNF and anisomycin was abolished in MSK1/2 double-knockout cells, whereas induction was significantly reduced in response to PMA or EGF. The MSK responsive elements were mapped to two AP (activator protein)-1-like elements in the Nur77 promoter. The induction of Nur77 was also blocked by A-CREB, suggesting that MSKs control Nur77 transcription by phosphorylating CREB bound to the two AP-1-like elements. Consistent with the decrease in Nur77 mRNA levels in the MSK1/2-knockout cells, it was also found that MSKs were required for the induction of Nur77 protein by PMA and TNF. MSKs were also found to be required for the transcription of two genes related to Nur77, Nurr1 and Nor1, which were also transcribed in a CREB- or ATF1 (activating transcription factor-1)-dependent manner. Downstream of anisomycin signalling, a second ERK-dependent pathway, independent of MSK and CREB, was also required for the transcription of Nurr1 and Nor1.

SUBMITTER: Darragh J

PROVIDER: S-EPMC1199668 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling.

Darragh Joanne J Soloaga Ana A Beardmore Victoria A VA Wingate Andrew D AD Wiggin Giselle R GR Peggie Mark M Arthur J Simon C JS

The Biochemical journal 20050901 Pt 3

MSK (mitogen- and stress-activated protein kinase) 1 and MSK2 are kinases activated downstream of either the ERK (extracellular-signal-regulated kinase) 1/2 or p38 MAPK (mitogen-activated protein kinase) pathways in vivo and are required for the phosphorylation of CREB (cAMP response element-binding protein) and histone H3. Here we show that the MSKs are involved in regulating the transcription of the immediate early gene Nur77. Stimulation of mouse embryonic fibroblasts with PMA, EGF (epidermal ...[more]

PMID: 15910281

Similar Datasets

Project description:NR4A orphan nuclear receptors are involved in multiple biological processes which are important in tumorigenesis such as cell proliferation, apoptosis, differentiation, and glucose utilization. The significance of NR4A family member NURR1 (NR4A2) in breast cancer etiology has not been elucidated. The purpose of this study was to ascertain the impact of NURR1 expression on breast transformation, tumor growth, and breast cancer patient survival.We determined the expression of NURR1 in normal breast versus breast carcinoma in tissue microarrays (immunohistochemistry), tissue lysates (immunoblot), and at the mRNA level (publically available breast microarrays). In addition NURR1 expression was compared among breast cancer patients in cohorts based on p53 expression, estrogen receptor ? expression, tumor grade, and lymph node metastases. Kaplan-Meier survival plots were used to determine the correlation between NURR1 expression and relapse free survival (RFS). Using shRNA-mediated silencing, we determined the effect of NURR1 expression on tumor growth in mouse xenografts.Results from breast cancer tissue arrays demonstrate a higher NURR1 expression in the normal breast epithelium compared to breast carcinoma cells (p???0.05). Among cases of breast cancer, NURR1 expression in the primary tumors was inversely correlated with lymph node metastases (p???0.05) and p53 expression (p???0.05). Clinical stage and histological grade were not associated with variation in NURR1 expression. In gene microarrays, 4 of 5 datasets showed stronger mean expression of NURR1 in normal breast as compared to transformed breast. Additionally, NURR1 expression was strongly correlated with increase relapse free survival (HR?=?0.7) in a cohort of all breast cancer patients, but showed no significant difference in survival when compared among patients whom have not been treated systemically (HR?=?0.91). Paradoxically, NURR1 silenced breast xenografts showed significantly decreased growth in comparison to control, underscoring a biphasic role for NURR1 in breast cancer progression.NURR1 function presents a dichotomy in breast cancer etiology, in which NURR1 expression is associated with normal breast epithelial differentiation and efficacy of systemic cancer therapy, but silencing of which attenuates tumor growth. This provides a strong rationale for the potential implementation of NURR1 as a pharmacologic target and biomarker for therapeutic efficacy in breast cancer.

Dataset Information

MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling.

Publications

MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets