Disease relevance of Rps6ka5

• Consistent with this, pharmacological inhibition of MSK1 enhanced the suppressive effects of As2O3 on the growth of primary leukemic progenitors from chronic myelogenous leukemia patients [1].

High impact information on Rps6ka5

• The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG-14 kinase [2].
• This activation of MSK1 leads to a rapid phosphorylation of histone H3 at Ser(10) [3].
• Our results provide evidence that oncogene-mediated activation of the Ras-mitogen-activated protein kinase signal transduction pathway elevates the activity of MSK1, resulting in the increased steady-state levels of phosphorylated H3, which may contribute to the chromatin decondensation and aberrant gene expression observed in these cells [3].
• In contrast to many other chromatin modifying enzymes, MSK1 was loosely bound in the nucleus and was not a component of the nuclear matrix [3].
• These studies demonstrated that MSK1, but not Rsk-2, was the H3 kinase activated in these cells [4].

Biological context of Rps6ka5

• MSK1 activation is also essential for M. avium-triggered NF-kappaB-dependent gene expression, presumably mediating nucleosomal modifications [5].
• We provide evidence that As2O3 induces activation of the mitogen- and stress-activated kinase 1 (MSK1) and downstream phosphorylation of its substrate, histone H3, in leukemia cell lines [1].
• We show here that MSK1 is the critical mediator of differentiation-induced H3 phosphoacetylation using both the chemical inhibitor H89 and RNA interference [6].
• Arsenic-induced apoptosis was enhanced in cells in which MSK1 expression was decreased using small interfering RNA and in Msk1 knock-out mouse embryonic fibroblasts, suggesting that this kinase is activated in a negative feedback regulatory manner to regulate As2O3 responses [1].
• Transfection experiments showed that an N-terminal mutant MSK1 or a C-terminal mutant MSK1 markedly blocked MSK1 activity [7].

Anatomical context of Rps6ka5

• The attenuation of MSK1 may therefore have potential benefit in restricting survival of pathogenic mycobacteria in macrophages [5].
• MSK1 is required for CREB phosphorylation in response to mitogens in mouse embryonic stem cells [8].
• The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells [9].
• MSK1 is also expressed in a subset of astroglia [10].
• In contrast, MSK1 is expressed at highest levels in striatal and olfactory tubercle neurons and to a lesser degree in cerebellar Purkinje cells [10].

Associations of Rps6ka5 with chemical compounds

• Ultraviolet B-induced phosphorylation of histone H3 at serine 28 is mediated by MSK1 [7].
• However, basal and forskolin-induced phosphorylation was similar, indicating that the MSK1 'knockout' did not prevent CREB phosphorylation by cyclic AMP-dependent protein kinase [8].
• Pretreatment with Ro 31-8220, an inhibitor of MSK1/2, induced cell death in LPS-stimulated RAW 264.7 cells [11].
• The effect of inhibition of mitogen and stress-activated protein kinases 1/2 (MSK1/2) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells was investigated [11].
• The kinase MSK1 is required for induction of c-fos by lysophosphatidic acid in mouse embryonic stem cells [12].

Physical interactions of Rps6ka5

• In addition, they indicate that MSK1 could act through CRE binding proteins to achieve c-fos promoter activation [12].

Enzymatic interactions of Rps6ka5

• We propose that persistent activation of the Ras-MAPK pathway and MSK1 resulting in the elevation of phosphorylated H3 levels may contribute to the aberrant gene expression observed in the oncogene-transformed cells [4].

Other interactions of Rps6ka5

• MSK1 mediates the phosphorylation of the transcription factor CREB accounting for its stimulatory effect on CRE-dependent gene expression [5].
• Both ERK and p38 MAPK activation converge to regulate the activation of mitogen- and stress-activated kinase 1 (MSK1) [5].
• They also suggest that MSK1 and MSK2 may play a role in these processes and hence are potential targets for the development of novel antiinflammatory drugs [13].
• In contrast, the TPA- and EGF-induced phosphorylation of CREB/ATF1 was barely detectable in MSK1-/- cells [8].
• The MSK responsive elements were mapped to two AP (activator protein)-1-like elements in the Nur77 promoter [14].

Analytical, diagnostic and therapeutic context of Rps6ka5

• We utilized immunohistochemistry to determine the cellular and subcellular localization of RSK1 and MSK1 in the adult mouse brain [10].

References