Sex hormone-binding globulin receptor signal transduction proceeds via a G protein

Nakhla, Atif M.; Leonard, Janet L.; Hryb, Daniel J.; Rosner, William

doi:10.1016/s0039-128x(98)00084-1

Cited by 79 publications

(44 citation statements)

References 14 publications

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“…Regulation of the PKA pathway by castration may involve both non-genomic and genomic effects of androgen. Testosterone is capable of elevating cAMP levels by binding to sex hormone-binding globulin associated with its receptor (Nakhla et al, 1999) which would result in increased PKA activity. In addition, or possibly alternatively, here we identify that androgen decreased expression of PKIB, which is a competitive inhibitor of PKA.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

et al. 2006

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Progression of prostate cancer to androgen independence is suspected to involve the androgen and protein kinase A (PKA) signaling pathways. Here for the first time, the transcriptomes associated with each pathway and common transcriptional targets in response to stimulation of both pathways were identified in human prostate cancer cells using Affymetrix GeneChip technology (Human Genome U133 plus2). Statistically significant changes in the levels of 858 genes in response to androgen and 303 genes in response to activation of the PKA pathway were determined using GeneSpring software. Expression of a subset of these genes (22) that were transcriptional targets for the androgen and/or PKA pathways were validated by reverse transcriptase-polymerase chain reaction and Western blot analyses. Application of small interfering RNAs to the androgen receptor (AR) revealed that in addition to KLK3, levels of expression of KLK2 and SESN1 were regulated by AR activated by both the androgen and PKA signaling pathways. SESN1 was identified as a gene repressed by activated AR. These results provide a broad view of the effects of the androgen and PKA signaling pathways on the transcriptional program of prostate cancer cells and indicate that only a limited number of genes are targeted by cross-talk between AR and PKA pathways.

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Section: Discussionmentioning

confidence: 99%

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

et al. 2006

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“…It is the major regulator of free estrogens and androgens in plasma (2)(3)(4); it is an initiating component of a signaling system for estrogens and androgens at the cell membrane that functions via a G protein (5) and cAMP (6 -9). The details of the working of these systems generate a model that is in need of clarification in a number of crucial respects.…”

mentioning

confidence: 99%

Sex Hormone-binding Globulin in the Human Prostate Is Locally Synthesized and May Act as an Autocrine/Paracrine Effector

Hryb¹,

Nakhla²,

Kahn³

et al. 2002

Journal of Biological Chemistry

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Sex hormone-binding globulin (SHBG) is a plasma protein synthesized and secreted by the liver. Its initial description stemmed from its ability to bind estrogens and androgens and its capacity to regulate the free concentration of the steroids that bind to it. Additionally, it participates in signal transduction for certain steroid hormones at the cell membrane. It binds with high affinity to a specific membrane receptor (R SHBG ) in prostate stromal and epithelial cells, wherein the SHBG⅐R SHBG complex forms. An appropriate steroid binds to this complex and results in increases of intracellular cAMP. These two disparate functions of SHBG, regulation of the concentration of free steroids in plasma and signal transduction in selected tissues, raise the question of how its synthesis and secretion might be regulated so as to best perform these two disparate functions. In this paper we demonstrate that SHBG is produced in human prostate cancer cell lines (LNCaP, DU 145, and PC 3) as well as in cultured human prostate epithelial and stromal cells. In addition, in tissue sections of human prostate, we demonstrate the presence of SHBG (immunocytochemistry) and SHBG mRNA (in situ hybridization). These observations are consistent with the hypothesis that SHBG, destined to participate in signaling at the cell membrane, is locally regulated and produced.The hepatically derived (1) plasma protein, sex hormonebinding globulin (SHBG) 1 has two apparently disparate functions. It is the major regulator of free estrogens and androgens in plasma (2-4); it is an initiating component of a signaling system for estrogens and androgens at the cell membrane that functions via a G protein (5) and cAMP (6 -9). The details of the working of these systems generate a model that is in need of clarification in a number of crucial respects. In this paper we present data that deal with the source of the SHBG for signaling at the cell membrane. These data support a model in which the source of SHBG for signaling is not the plasma, but rather the target cells themselves.

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“…SHBG is produced by liver and is down-regulated by insulin levels (32)(33)(34) . Along with the well-known role of transport protein SHBG is also involved in other independent functions (32,(35)(36) . Emerging evidence attests that even sex hormones bound to SHBG may directly mediate cell-surface signaling, cellular delivery, and biologic action of sex hormones (35)(36) .…”

Section: Shbg and Padmentioning

confidence: 99%

The Relationship between Sex Hormones, Sex Hormone Binding Globulin and Peripheral Artery Disease in Older Persons

Cattabiani¹,

Ceda²,

Lauretani³

et al. 2011

CLINICAL - Male Reproductive Endocrinology I

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Objective-The prevalence of peripheral artery disease (PAD) increases with aging and is higher in persons with metabolic syndrome and diabetes. PAD is associated with adverse outcomes, including frailty and disability. The protective effect of testosterone and sex hormone binding globulin (SHBG) for diabetes in men suggests that the biological activity of sex hormones may affect PAD, especially in older populations.Methods-Nine hundred and twenty-one elderly subjects with data on SHBG, testosterone (T), estradiol (E2) were selected from InCHIANTI study. PAD was defined as an Ankle-Brachial Index (ABI) <0.90. Logistic regression models adjusted for age (Model 1), age, BMI, insulin, interleukin-6, physical activity, smoking, chronic diseases including metabolic syndrome (Model © 2012 Elsevier Ireland Ltd. All rights reserved.Corresponding author: Marcello Maggio, MD, PhD, Department of Clinical and Experimental Medicine, Section of Geriatrics, University of Parma, via Gramsci 14, 43100 Parma, Italy., Phone: 0039-0521-703916, marcellomaggio2001@yahoo.it. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 2), and a final model including also sex hormones (Model 3) were performed to test the relationship between SHBG, sex hormones and PAD. DisclosureResults-The mean age (± SD) of the 419 men and 502 women was 75.0 ± 6.8 years (Sixty two participants (41 men, 21 women) had ABI<0.90. Men with PAD had SHBG levels lower than men without PAD (p=0.03). SHBG was negatively and independently associated with PAD in men (p=0.028). but not in women. The relationship was however attenuated after adjusting for sex hormones (p=0.07). The E2 was not significantly associated with PAD in both men and women. In women, but not in men, T was positively associated with PAD, even after adjusting for multiple confounders, including E2 (p=0.01).Conclusions-Low SHBG and high T levels are significantly and independently associated with the presence of PAD in older men and women, respectively.

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Sex hormone-binding globulin receptor signal transduction proceeds via a G protein

Cited by 79 publications

References 14 publications

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

Sex Hormone-binding Globulin in the Human Prostate Is Locally Synthesized and May Act as an Autocrine/Paracrine Effector

The Relationship between Sex Hormones, Sex Hormone Binding Globulin and Peripheral Artery Disease in Older Persons

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