Mechanism of GnRH receptor signaling on gonadotropin release and gene expression in pituitary gonadotrophs

Shacham, Sharon; Harris, Dagan; Ben-Shlomo, Herzel; Cohen, I.; Bonfil, David; Przedecki, Fiorenza; Lewy, Hadas; Ashkenazi, Israel; Seger, Rony; Naor, Zvi

doi:10.1016/s0083-6729(01)63003-6

Cited by 49 publications

(30 citation statements)

References 110 publications

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“…Fig. 5A illustrates the feasibility of this approach, since when Myc-ubiquitin was expressed alone, GnRH-induced Mycpolyubiquitination of endogenous receptors (upper panel, lanes [1][2][3] paralleled the profile of endogenous ubiquitin incorporation into type I receptors (Fig. 2C) , compare lanes 1-3 with lanes 4 -6) considerably enhanced Myc-polyubiquitination (upper panel, lanes 4 -6), indicating that exogenous receptors are efficiently polyubiquitinated.…”

Section: Fig 2 Proteasome Inhibitors Block Insp 3 Receptor Down-regmentioning

confidence: 88%

“…Hormone-induced secretion from anterior pituitary cells is modulated at many different levels, and among these is regulation of the activity and abundance of receptors involved in signal transduction (1,2). Indeed, recent studies on the ␣T3-1 mouse gonadotrope cell line have indicated that the suppression of secretion from gonadotropes in patients treated chronically with gonadotropin-releasing hormone (GnRH) 1 receptor agonists (2, 3) may result from a reduction in the expression of inositol 1,4,5-trisphosphate (InsP 3 ) receptors (2,4,5).…”

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confidence: 99%

“…Indeed, recent studies on the ␣T3-1 mouse gonadotrope cell line have indicated that the suppression of secretion from gonadotropes in patients treated chronically with gonadotropin-releasing hormone (GnRH) 1 receptor agonists (2, 3) may result from a reduction in the expression of inositol 1,4,5-trisphosphate (InsP 3 ) receptors (2,4,5). InsP 3 receptors are a family of three proteins (termed type I, II, and III receptors) that form tetrameric ion channels in endoplasmic reticulum (ER) membranes, and upon binding of InsP 3 , the channels open, and Ca 2ϩ stored within the ER flows into the cytoplasm (6 -8).…”

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confidence: 99%

“…: 315-464-7956; Fax: 315-464-8014; E-mail: wojcikir@mail.upstate.edu. 1 The abbreviations used are: GnRH, gonadotropin-releasing hormone; InsP 3 likely to limit the accumulation of ubiquitinated receptors and that InsP 3 receptor ubiquitination is Zn 2ϩ -dependent. Importantly, we also used ␣T3-1 cells to develop conditions for the analysis of exogenous InsP 3 receptor ubiquitination, and by expressing mutant receptors, we show that InsP 3 binding is important in triggering this event but that phosphorylation is not.…”

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confidence: 99%

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Ubiquitination and Proteasomal Degradation of Endogenous and Exogenous Inositol 1,4,5-Trisphosphate Receptors in αT3-1 Anterior Pituitary Cells

Wojcikiewicz

Webster

et al. 2003

Journal of Biological Chemistry

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276, 3123-3129). In the current study, we sought to define the mechanism behind this adaptive response. We show that GnRH induces a rapid and dramatic increase in InsP 3 receptor polyubiquitination and that proteasome inhibitors block InsP 3 receptor down-regulation and cause the accumulation of polyubiquitinated receptors. Thus, the ubiquitin/proteasome pathway is active in ␣T3-1 cells, and GnRH regulates the levels of InsP 3 receptors via this mechanism. Given these findings and further characterization of this system, we also examined the possibility that ␣T3-1 cells could be used to examine the ubiquitination of exogenous InsP 3 receptors introduced by cDNA transfection. This was found to be the case, since exogenous wild-type InsP 3 receptors, but not bindingdefective mutant receptors, were polyubiquitinated in a GnRH-dependent manner, and agents that inhibited the polyubiquitination of endogenous receptors also inhibited the polyubiquitination of exogenous receptors. Further, we used this system to determine whether phosphorylation was involved in triggering InsP 3 receptor polyubiquitination. This was not the case, since mutation of serine residues 1588 and 1755 (the predominant phosphorylation sites in the type I receptor) did not inhibit polyubiquitination. In total, these data show that the ubiquitin/proteasome pathway is active in anterior pituitary cells, that this pathway targets both endogenous and exogenous InsP 3 receptors in GnRH-stimulated ␣T3-1 cells, and that, in contrast to the situation for many other substrates, phosphorylation does not trigger InsP 3 receptor polyubiquitination.

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Section: Fig 2 Proteasome Inhibitors Block Insp 3 Receptor Down-regmentioning

confidence: 88%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Ubiquitination and Proteasomal Degradation of Endogenous and Exogenous Inositol 1,4,5-Trisphosphate Receptors in αT3-1 Anterior Pituitary Cells

Wojcikiewicz

Webster

et al. 2003

Journal of Biological Chemistry

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“…The avian egg-production process is strictly controlled by the hypothalamic-pituitary-gonadal axis (Kuo et al, 2005). Gonadotropin-releasing hormone (GnRH) is a key hormone located at the pinnacle of this axis (Shacham et al, 2001). GnRH, binding with its receptor GnRHR, stimulates gonadotrophin secretion from the pituitary gland and then evokes steroidogenesis in the gonads, resulting in egg production in hens (Shacham et al, 2001;Proudman et al, 2006;Sonez et al, 2010).…”

Section: Introductionmentioning

confidence: 99%