Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line. Role of STAT pathway.

Ray, David; Ren, Song; Melmed, Shlomo

doi:10.1172/jci118615

Cited by 149 publications

(110 citation statements)

References 40 publications

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“…Here, we found that CRH stimulated the rat POMC promoter K480/C63 construct, while pCPT-cAMP stimulated the rat POMC promoter K480/C63 construct to a large degree. This result coincides with those of previous reports (Jeannotte et al 1987, Ray et al 1996, Kovalovsky et al 2002, Mynard et al 2004. The low promoter activation of CRH treatment might be due to low cAMP generation, because there are some reports that described low and transient cAMP accumulation on CRH stimulation in AtT-20 cells (Litvin et al 1984, Nikodemova et al 2003.…”

Section: Discussionsupporting

confidence: 94%

Corticotropin-releasing hormone or dexamethasone regulates rat proopiomelanocortin transcription through Tpit/Pitx-responsive element in its promoter

Murakami¹,

Tanaka²,

Kudo³

et al. 2007

Journal of Endocrinology

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Tpit/Pitx-responsive element (Tpit/PitxRE), which binds transcription factors Tpit and Pitx1, confers cell-type specific expression of proopiomelanocortin (POMC) gene in pituitary corticotrops where the gene expression is mainly regulated by corticotropin-releasing hormone (CRH) and glucocorticoids (Gcs). CRH stimulates POMC gene expression, which is mediated by the accumulation of intracellular cAMP and requires binding of Nur factors to Nur-responsive element (NurRE). Gcs antagonize NurRE-dependent POMC gene expression through direct interaction between glucocorticoid receptors and Nur factors. We examined whether Tpit/PitxRE and NurRE are involved in CRH/cAMP-induced activation and Gc-induced repression of POMC gene expression by reporter assay in AtT-20 corticotropic cells. Deletion and mutation of Tpit/PitxRE markedly reduced basal activity of the promoter, and those of NurRE decreased the levels of the CRH/cAMP-induced activation. Nifedipine, KN-62, and W-7, specific inhibitors of the L-type calcium channel, calmodulin-dependent protein kinase II, and calmodulin respectively, attenuated CRH/cAMP-induced activation of promoters with three copies of either Tpit/PitxRE or NurRE, indicating that both Tpit/PitxRE and NurRE mediate CRHinduced activation of POMC gene expression in a calciumdependent manner. Deletion and mutation of Tpit/PitxRE abolished dexamethasone (DEX)-induced repression of POMC gene expression, while those of NurRE did not, indicating that Tpit/PitxRE predominantly mediates Gc-induced repression of POMC transcription. However, DEX treatment attenuated activities of promoters with three copies of either Tpit/PitxRE or NurRE, suggesting that Gcs act at NurRE as well as Tpit/PitxRE to repress POMC gene expression. We conclude that Tpit/PitxRE is an important element by which CRH and Gcs regulate the POMC gene expression.

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Section: Discussionsupporting

confidence: 94%

Corticotropin-releasing hormone or dexamethasone regulates rat proopiomelanocortin transcription through Tpit/Pitx-responsive element in its promoter

Murakami¹,

Tanaka²,

Kudo³

et al. 2007

Journal of Endocrinology

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“…Model of interaction and negative autoregulatory feedback of SOCS-3 protein on POMC and SOCS-3 gene expression. The LIF-induced signaling cascade in the corticotroph cell envolves tyrosine phosphorylation of gp130, STAT-3, and STAT-1 (15,23,26,27). LIF induces gene expression of POMC (28) and SOCS-3 in the corticotroph cell in a STAT-3 dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro experiments using human fetal pituitary cells (23) and the corticotroph cell line AtT-20 (24,25) showed a profound synergistic action of LIF and corticotropin-releasing hormone on POMC gene expression and ACTH secretion. The LIF-induced signaling cascade in the corticotroph cell involves phosphorylation of gp130, STAT-3, and STAT-1 (15,23,26,27), and LIF-induced POMC expression and ACTH secretion is STAT-3 dependent (28). SOCS-3 gene expression is rapidly induced by LIF in the pituitary in vivo and in corticotroph AtT-20 cells in vitro (15).…”

mentioning

confidence: 99%

Autoregulation of pituitary corticotroph SOCS-3 expression: Characterization of the murine SOCS-3 promoter

Auernhammer

Bousquet

Melmed

1999

Proc. Natl. Acad. Sci. U.S.A.

269

224

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Pituitary corticotroph SOCS-3 is a novel intracellular regulator of leukemia inhibitory factor (LIF)-mediated proopiomelanocortin gene expression and adrenocorticotropic hormone (ACTH) secretion, inhibiting LIF-activated Janus kinase-signal transducers and activators of transcription (STAT) signaling in a negative autoregulatory loop. We now demonstrate in corticotroph AtT-20 cells that LIF-stimulated endogenous SOCS-3 mRNA expression is blocked in stable transfectants of SOCS-3 wild type or in dominant negative STAT-3 mutants, respectively. We characterized Ϸ3.8-kb genomic 5 sequence of murine SOCS-3, including Ϸ2.9-kb sequence upstream of the transcription start site (؉1), which was determined by 5 rapid amplification of cDNA ends and RNase protection assay. Different 5 constructs were cloned into the pGL3Basic vector, and luciferase activity was assayed in transiently transfected ACTH-secreting corticotroph AtT-20 cells. A STAT-1͞STAT-3 binding element, located at nucleotides ؊72 to ؊64, was essential for LIF stimulation of SOCS-3 promoter activity. LIF induced 10-fold increased luciferase activity in a wild-type construct spanning ؊2757 to ؉929 bases. However, deletion or point mutation of the STAT-1͞STAT-3 binding element abrogated LIF action (2-to 3-fold). Electrophoretic mobility-shift assay analysis confirmed specific binding of STAT-1 and STAT-3 to this region. These results characterize the genomic 5 region of murine SOCS-3 and identify an important STAT-1͞STAT-3 binding element therein. Thus, LIFstimulated SOCS-3 gene expression is at least in part mediated by STAT-3 and STAT-1. The cytokine inhibitor SOCS-3 acts in a negative loop to autoregulate its own gene expression, thus limiting its accumulation in the corticotroph cell. These results demonstrate a mechanism for corticotroph plasticity with rapid

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“…The membrane was washed in Trisbuffered saline with 0·1% Tween 20, and the secondary antibody, anti mouse-hrp (Amersham) used at 1:2000 dilution in blocking buffer. Detection was by enhanced chemiluminescence (ECL) as previously described (Ray et al 1996b).…”

Section: Immunoblottingmentioning

confidence: 99%

Genetic engineering of the glucocorticoid receptor by fusion with the herpes viral protein VP22 causes selective loss of transactivation

Soden¹,

Stevens²,

Ray³

2002

Journal of Endocrinology

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The development of methods for engineering proteins with novel properties opens the way to manipulating intracellular processes in a therapeutically useful way. Glucocorticoids, acting via glucocorticoid receptors (GR), are potent anti-inflammatory agents, acting to oppose nuclear factor kappa B (NF B) function. The herpes viral protein, VP22, has been reported to confer intercellular trafficking activity on 'cargo' proteins, potentially facilitating gene therapy with intracellular proteins.VP22GR, resulting from the addition of VP22 to the N terminal of GR, was equipotent with the wild-type GR in opposing NF B p65-driven expression of an NF B reporter gene. Surprisingly, VP22GR was incapable of inducing transactivation of positive glucocorticoid reporter genes (MMTV-luc and TAT3-luc). Furthermore, the VP22GR had powerful dominant negative activity on both endogenous and exogenous GR transactivation. VP22GR was cytoplasmic in quiescent cells, and after hormone addition underwent nuclear translocation to share the same distribution as the GR. The ability of the VP22GR to selectively confer and enhance glucocorticoid-dependent transrepression of NF B may be of use therapeutically in e.g. transplant rejection, inflammatory arthritis or asthma.

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Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line. Role of STAT pathway.

Cited by 149 publications

References 40 publications

Corticotropin-releasing hormone or dexamethasone regulates rat proopiomelanocortin transcription through Tpit/Pitx-responsive element in its promoter

Corticotropin-releasing hormone or dexamethasone regulates rat proopiomelanocortin transcription through Tpit/Pitx-responsive element in its promoter

Autoregulation of pituitary corticotroph SOCS-3 expression: Characterization of the murine SOCS-3 promoter

Genetic engineering of the glucocorticoid receptor by fusion with the herpes viral protein VP22 causes selective loss of transactivation

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