Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome

Trivier, Elisabeth; Cesare, Dario De; Jacquot, Sylvie; Pannetier, Solange; Zackai, Elaine H.; Young, Ian; Mandel, Jean‐Louis; Sassone–Corsi, Paolo; Hanauer, André

doi:10.1038/384567a0

Cited by 385 publications

(286 citation statements)

References 21 publications

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“…However, precise substrates for each member of the family are less well understood. RPS6KA3 was shown to be inactivated by mutations in the X-linked disorder Coffin-Lowry syndrome yet the highly related RPS6KA1 and RPS6KA2 kinases were found to be expressed at normal levels in these patients (Trivier et al, 1996;Bruning et al, 2000). This has been further confirmed by the generation of RPS6KA3 À/À mice (Dufresne et al, 2001).…”

Section: Discussionmentioning

confidence: 81%

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

et al. 2006

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We had previously defined by allele loss studies a minimal region at 6q27 (between D6S264 and D6S297) to contain a putative tumour suppressor gene. The p90 ribosomal S6 kinase-3 gene (p90 Rsk-3, RPS6KA2) maps in this interval. It is a serine-threonine kinase that signals downstream of the mitogen-activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells. Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced proliferation, caused G1 arrest, increased apoptosis, reduced levels of phosphorylated extracellular signal-regulated kinase and altered other cell cycle proteins. In contrast, small interfering RNA against RPS6KA2 showed the opposite effect in 41M cells. The above results suggest that RPS6KA2 is a putative tumour suppressor gene to explain allele loss at 6q27.

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Section: Discussionmentioning

confidence: 81%

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

et al. 2006

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“…It was puri®ed as the main NGF-induced CREB-kinase in PC12 cells (Xing et al, 1996). Mutations in the RSK2 gene and loss of RSK2 activity have also been associated with Co n-Lowry syndrome (CLS) which is characterized by severe psychomotor retardation, facial and digital dymorphisms, and progressive skeletal deformations (Trivier et al, 1996;Young, 1988). EGF-induced CREB phosphorylation was lost in ®broblasts from CLS patients while there was no change in cAMP, UV or serum induced CREB phosphorylation (De Cesare et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

2000

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The c-fos enhancer can be activated by many signaling pathways through distinct elements of the enhancer. The enhancer contains at its core the serum response element (SRE) that binds serum response factor (SRF). On the 5' side of the SRE is a site for p62 TCF which binds only when SRF is bound as well. p62 TCF is encoded by three ets-related genes, Elk-1, SAP1 and SAP2. Each of these factors contain a transcriptional activation domain that is activated by phosphorylation by MAP kinases. On the 3' side of the SRE is the`c-fos AP1 site' (FAP1) whose role has been less clear. We ®nd here that the FAP1 site contributes strongly to phorbol ester (TPA) and Erk MAP kinase activation of the c-fos enhancer and that both the p62 TCF and FAP1 sites are required for e ective activation of the enhancer. We further ®nd that the FAP1 site binds ATF1 and CREB from HeLa nuclear extracts and that the phosphorylation of these factors is induced by TPA. ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62 TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.

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“…Recent evidence indicated that Rsk-2 was required for EGF stimulated H3 SerlO phosphorylation in vivo (Trivier et al, 1996;Sassone-Corsi et al, 1999).…”

Section: Chapter 4 Results and Discussionmentioning

confidence: 99%

“…Genetic and biochemical studies in yeast, D. melanogaster, and human cells have identified a new class of multiple protein complexes that utilize ATP to remodel nucleosome and chromatin structure (Bjorklund et al, 1999;Trivier et al, 1996;Tyler and Kadonaga, 1999;Workman and Kingston, 1998). In D. melanogaster, four different ATP-dependent chromatin remodeling complexes have been identified.…”

Section: Atp Dependent Chromatin Remodeling Machinerymentioning

confidence: 99%

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Drosophila JIL-1 kinase mediates histone H3 Ser10 phosphorylation, maintains higher order chromatin structure, and is implicated in dosage compensation

Wang

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Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome

Cited by 385 publications

References 21 publications

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

Drosophila JIL-1 kinase mediates histone H3 Ser10 phosphorylation, maintains higher order chromatin structure, and is implicated in dosage compensation

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