The role of p90 ribosomal S6 kinases (RSKs) in Steroid signalling
The p90 ribosomal S6 kinases (RSKs) are a family of serine/threonine kinases consisting of four isoforms (RSK1-4), which regulate key cellular processes including cell cycle, proliferation, motility and survival. Among the several transcription factors targeted by RSKs, several studies have identified the Steroid Receptors (SRs) as substrates of the RSKs. SRs are a subfamily of the nuclear receptor superfamily consisting of five proteins (androgen, glucocorticoid, estrogen, progesterone and mineralocorticoid receptors). These proteins regulate gene expression thus are involved in crucial biological processes, including organ development and maintenance, the immune system, neuroprotection and metabolic homeostasis. Importantly, SRs are the main drivers of hormone driven cancers. Therefore, we hypothesised that the RSKs could play an important part in SR signalling within hormone driven cancer development and progression. This was investigated using recombinant DNA techniques to incorporate the RSKs genes into the mammalian expression vector PCDNA 3.1(+) and to produce phospho-mimetic mutants. Luciferase assays were used to determine optimal hormone and DNA concentrations, the role of RSKs on SR activity, the activity of the endogenous MAPK pathway and the significance of phosphorylation state. The PMA experiments indicated that in most cases PMA does not induce a significant change to RSK activity, thus the endogenous MAPK pathway is sufficiently active. The mutant experiments suggested that the phospho-mimetic mutation used does not cause constitutive activation of the RSKs. Together considering all experiments it was illustrated that the RSKs have differential effects on SR signalling. All the RSKs increased AR and GR activity despite some contradictions within the data. RSK4 significantly decreased ERα activity and RSK3 significantly increased PR activity.
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