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Int. J. Mol. Sci. 2017, 18(7), 1453; doi:10.3390/ijms18071453

Role of Hormones in the Regulation of RACK1 Expression as a Signaling Checkpoint in Immunosenescence

1
Department of Drug Sciences, Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia, Italy
2
Scuola Universitaria Superiore IUSS Pavia, Piazza della Vittoria 15, 27100 Pavia, Italy
3
Laboratory of Toxicology, Department of Environmental Science and Policy, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
*
Author to whom correspondence should be addressed.
Received: 9 May 2017 / Revised: 22 June 2017 / Accepted: 30 June 2017 / Published: 6 July 2017
(This article belongs to the Special Issue Immunology of Aging)
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Abstract

Immunosenescence defines the decline in immune function that occurs with aging. This has been associated, at least in part, with defective cellular signaling via protein kinase C (PKC) signal transduction pathways. Our data suggest reduced PKC activation and consequently reduced response to lipopolysaccharide (LPS) stimulation and cytokine release. The lack of PKC activation seems to be dependent on the reduced expression of the receptor for activated C kinase 1 (RACK1), a scaffolding protein involved in multiple signal transduction cascades. The defective expression of RACK1 may be dependent on age-related alteration of the balance between the adrenal hormones cortisol and dehydroepiandrosterone (DHEA). DHEA levels reduce with aging, while cortisol levels remain substantially unchanged, resulting in an overall increase in the cortisol:DHEA ratio. These hormonal changes are significant in the context of RACK1 expression and signaling function because DHEA administration in vivo and in vitro can restore the levels of RACK1 and the function of the PKC signaling cascade in aged animals and in human cells. In contrast, there is evidence that cortisol can act as a negative transcriptional regulator of RACK1 expression. The rack1 gene promoter contains a glucocorticoid responsive element that is also involved in androgen signaling. Furthermore DHEA may have an indirect influence on the post-transcriptional regulation of the functions of the glucocorticoid receptor. In this review, we will examine the role of the hormonal regulation of rack1 gene transcriptional regulation and the consequences on signaling and function in immune cells and immunosenescence. View Full-Text
Keywords: aging; immunosenescence; signal transduction; protein kinase C; transcriptional regulation; cortisol; dehydroepiandrosterone; glucocorticoid receptors. aging; immunosenescence; signal transduction; protein kinase C; transcriptional regulation; cortisol; dehydroepiandrosterone; glucocorticoid receptors.
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Racchi, M.; Buoso, E.; Ronfani, M.; Serafini, M.M.; Galasso, M.; Lanni, C.; Corsini, E. Role of Hormones in the Regulation of RACK1 Expression as a Signaling Checkpoint in Immunosenescence. Int. J. Mol. Sci. 2017, 18, 1453.

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