Transcriptional regulation of RACK1 and modulation of its expression: Role of steroid hormones and significance in health and aging

Buoso, Erica; Galasso, Marilisa; Serafini, Melania Maria; Ronfani, Melania; Lanni, Cristina; Corsini, Emanuela; Racchi, Marco

doi:10.1016/j.cellsig.2017.02.010

Cited by 20 publications

(18 citation statements)

References 77 publications

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“…However, there is no clear indication of the interaction of DHEA with a nuclear receptor with canonical transcriptional activity. As the contrasting effect of DHEA on RACK1 expression cannot be explained by a direct interaction on the promoter region or with simple pharmacological antagonism, a number of different indirect mechanisms have been explored (Reviewed in [ 22 ]).…”

Section: The Critical Involvement Of Hormonal Balance Affecting Ramentioning

confidence: 99%

“…The extensive investigation of the relationship between RACK1 and its binding partners has led to the realization that RACK1 interacts with numerous proteins (mostly engaged in signaling), either directly or as a part of a larger complex in distinct cellular compartments [ 3 , 30 ]. Some of the signaling partners include Mitogen Activated Protein Kinase (MAPK), Jun-N-terminal Kinase (JNK), and cAMP specific phosphodiesterase PDE4D5, as well as Src kinase and integrins [ 22 , 31 , 32 , 33 ]. The functions supported by these interactions range from cell growth and survival to cell mobility and suggest a potential role for RACK1 in the development and spread of cancerous cells.…”

Section: Rack1 and Its Transcriptional Regulationmentioning

confidence: 99%

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

Racchi

Buoso

Ronfani

et al. 2017

IJMS

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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.

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Section: The Critical Involvement Of Hormonal Balance Affecting Ramentioning

confidence: 99%

Section: Rack1 and Its Transcriptional Regulationmentioning

confidence: 99%

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

Racchi

Buoso

Ronfani

et al. 2017

IJMS

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“…Hence, they recognise a response element usually described as a canonical androgen/glucocorticoid response element (ARE/GRE) characterised by a well-conserved 5 -hexamer and a less stringent sequence requirement for the 3 -hexamer. Therefore, the GRE sequence described in the RACK1 gene promoter is also a cis-regulatory target of AR [17,18,20] as further confirmed by nandrolone induced-RACK1 expression and the immune response [18]. These data demonstrate that a complex hormonal balance, between cortisol and androgens, can regulate RACK1 expression and immune activation [20] thus supporting RACK1 as a possible target of EDCs with a consequent modulation of innate immune functionality and cell proliferation [16,18].…”

Section: Rack1 As a Possible Target Of Edcsmentioning

confidence: 58%

“…The role of EDCs in modulating the tumour microenvironment has not been elucidated, but is of pivotal interest. In this regard, the scaffold protein Receptor for Activated C Kinase 1 (RACK1) is an EDC target in the immune context [17][18][19][20] and an important molecular player for cancer progression (reviewed in [21]). Therefore, EDCs-mediated RACK1 regulation in both contexts could be central to understand the role of endocrine-mediated microenvironment regulation and to link innate immune activation with cancer progression through RACK1.…”

Section: Introductionmentioning

confidence: 99%

Endocrine-Disrupting Chemicals’ (EDCs) Effects on Tumour Microenvironment and Cancer Progression: Emerging Contribution of RACK1

Buoso

Masi

Racchi

et al. 2020

IJMS

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Endocrine disruptors (EDCs) can display estrogenic and androgenic effects, and their exposure has been linked to increased cancer risk. EDCs have been shown to directly affect cancer cell regulation and progression, but their influence on tumour microenvironment is still not completely elucidated. In this context, the signalling hub protein RACK1 (Receptor for Activated C Kinase 1) could represent a nexus between cancer and the immune system due to its roles in cancer progression and innate immune activation. Since RACK1 is a relevant EDCs target that responds to steroid-active compounds, it could be considered a molecular bridge between the endocrine-regulated tumour microenvironment and the innate immune system. We provide an analysis of immunomodulatory and cancer-promoting effects of different EDCs in shaping tumour microenvironment, with a final focus on the scaffold protein RACK1 as a pivotal molecular player due to its dual role in immune and cancer contexts.

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“…In human BC cells, the receptor for activated C kinase 1 (RACK1) has been identified as a possible prognostic marker and drug target 2 due to its critical role in cancer cell migration and invasion [3][4][5][6] . Changes in RACK1 levels have been found to subvert physiological functions, leading to the development and maintenance of several BC hallmarks [6][7][8][9] . Indeed, data mining analyses (Chin, 130; Bertucci 266; Booser, 508) revealed that elevated RACK1 expression negatively correlates with overall survival (OS) 10 , thus indicating that RACK1 over-expression associates with poor clinical outcome 2 .…”

Section: Introductionmentioning

confidence: 99%

OXER1 and RACK1-associated pathway: a promising drug target for breast cancer progression

et al. 2020

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Recent data indicate that receptor for activated C kinase 1 (RACK1) is a putative prognostic marker and drug target in breast cancer (BC). High RACK1 expression is negatively associated with overall survival, as it seems to promote BC progression. In tumors, RACK1 expression is controlled by a complex balance between glucocorticoids and androgens. Given the fact that androgens and androgenic derivatives can inhibit BC cell proliferation and migration, the role of androgen signaling in regulating RACK1 transcription in mammary tumors is of pivotal interest. Here, we provide evidence that nandrolone (19-nortosterone) inhibits BC cell proliferation and migration by antagonizing the PI3K/Akt/NF-κB signaling pathway, which eventually results in RACK1 downregulation. We also show that nandrolone impairs the PI3K/Akt/NF-κB signaling pathway and decreases RACK1 expression via binding to the membrane-bound receptor, oxoeicosanoid receptor 1 (OXER1). High levels of OXER1 are observed in several BC cell lines and correlate with RACK1 expression and poor prognosis. Our data provide evidence on the role played by the OXER1-dependent intracellular pathway in BC progression and shed light on the mechanisms underlying membrane-dependent androgen effects on RACK1 regulation. Besides the mechanistic relevance, the results of the study are of interest from a translational prospective. In fact, they identify a new and actionable pathway to be used for the design of innovative and rational therapeutic strategies in the context of the personalized treatment of BC. In addition, they draw attention on nandrolone-based compounds that lack hormonal activity as potential anti-tumor agents.

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Transcriptional regulation of RACK1 and modulation of its expression: Role of steroid hormones and significance in health and aging

Cited by 20 publications

References 77 publications

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

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

Endocrine-Disrupting Chemicals’ (EDCs) Effects on Tumour Microenvironment and Cancer Progression: Emerging Contribution of RACK1

OXER1 and RACK1-associated pathway: a promising drug target for breast cancer progression

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