Desensitization of the JAK2/STAT5 GH signaling pathway associated with increased CIS protein content in liver of pregnant mice

Miquet, Johanna G.; Sotelo, Ana I.; Bartke, Andrzej; Turyn, Daniel

doi:10.1152/ajpendo.00085.2005

Cited by 7 publications

(9 citation statements)

References 77 publications

(101 reference statements)

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“…2002, Miquet et al . 2004, 2005). This implies that this signaling pathway would not be involved in the proliferative effect of overexpressed GH.…”

Section: Introductionmentioning

confidence: 99%

GH modulates hepatic epidermal growth factor signaling in the mouse

González

Díaz²,

Miquet³

et al. 2009

Journal of Endocrinology

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Epidermal growth factor (EGF) is a key regulator of cell survival and proliferation involved in the pathogenesis and progression of different types of cancer. The EGF receptor (EGFR) is activated by binding of the specific ligand but also by transactivation triggered by different growth factors including GH. Chronically, elevated GH levels have been associated with the progression of hepatocellular carcinoma. Considering EGF and GH involvement in cell proliferation and their signaling crosstalk, the objective of the present study was to analyze GH modulatory effects on EGF signaling in liver. For this purpose, GH receptor-knockout (GHR-KO) and GH-overexpressing transgenic mice were used. EGFR content was significantly decreased in GHR-KO mice. Consequently, EGF–induced phosphorylation of EGFR, AKT, ERK1/2, STAT3, and STAT5 was significantly decreased in these mice. In contrast, EGFR content as well as its basal tyrosine phosphorylation was increased in transgenic mice overexpressing GH. However, EGF stimulation caused similar levels of EGFR, AKT, and ERK1/2 phosphorylation in normal and transgenic mice, while EGF induction of STAT3 and STAT5 phosphorylation was inhibited in the transgenic mice. Desensitization of the STATs was related to decreased association of these proteins to the EGFR and increased association between STAT5 and the tyrosine phosphatase SH2-containing phosphatase-2. While GHR knockout is associated with diminished expression of the EGFR and a concomitant decrease in EGF signaling, GH overexpression results in EGFR overexpression with different effects depending on the signaling pathway analyzed: AKT and ERK1/2 pathways are induced by EGF, while STAT3 and STAT5 activation is heterologously desensitized.

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“…2002, Miquet et al . 2004, 2005). This implies that this signaling pathway would not be involved in the proliferative effect of overexpressed GH.…”

Section: Introductionmentioning

confidence: 99%

GH modulates hepatic epidermal growth factor signaling in the mouse

González

Díaz²,

Miquet³

et al. 2009

Journal of Endocrinology

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“…mGH was determined by RIA as already described [25]. mGH RIA kit was obtained through the National Hormone and Pituitary Program, NIDDK, NIH, USA.…”

Section: Mgh Determinationmentioning

confidence: 99%

Vitamin D3 cannot revert desensitization of growth hormone (GH)-induced STAT5-signaling in GH-overexpressing mice non-calcemic tissues

Sotelo

Miquet

González

et al. 2008

Growth Hormone & IGF Research

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“…Previous in vivo work has demonstrated that chronic exposure of rats to GH results in desensitization of the JAK2/STAT5b signaling pathway (22,44). This phenomenon has been attributed to GH-induced changes in the expression of the negative regulators of GH signaling, the SOCS, and the CIS proteins (18).…”

Section: Discussionmentioning

confidence: 99%

The effect of different patterns of growth hormone administration on the IGF axis and somatic and skeletal growth of the dwarf rat

Westwood

Maqsood²,

Solomon³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Westwood M, Maqsood AR, Solomon M, Whatmore AJ, Davis JR, Baxter RC, Gevers EF, Robinson IC, Clayton PE. The effect of different patterns of growth hormone administration on the IGF axis and somatic and skeletal growth of the dwarf rat. Am J Physiol Endocrinol Metab 298: E467-E476, 2010. First published October 27, 2009 doi:10.1152/ajpendo.00234.2009.-Normal childhood growth is determined by ultradian and infradian variations in GH secretion, yet GH treatment of children with short stature is restricted to daily fixed doses. We have used GH-deficient dwarf rats to determine whether variable GH dose regimens promote growth more effectively than fixed doses. Animals were treated with saline or 4.2 mg of recombinant bovine GH given as 1) 700 g/wk in 100 g/day doses, 2) alternating weekly doses of 966 (138 g/day) or 434 g (62 g/day), or 3) 700 g/wk in randomized daily doses (5-250 g/day). Body weight and length were measured weekly. Femur and tibia lengths and internal organ, fat pad, and muscle weights were recorded at the end of the study (6 wk); blood was collected for IGF axis measurements. GH promoted femur [F(3,60) 60) ϭ 6.70, P Ͻ 0.05] levels. IGF-I levels correlated with final weight (r ϭ 0.45, P Ͻ 0.05) and length (r ϭ 0.284, P Ͻ 0.05) in the whole cohort, but within each group, growth parameters correlated with serum IGF-I only in animals treated with random GH doses. The variable regimens promoted femur length (P Ͻ 0.05) and muscle (P Ͻ 0.05) and kidney (P Ͻ 0.05) weight more effectively than treatment with the fixed regimen. This study demonstrates that aspects of growth are improved following introduction of infradian variation to GH treatment in a GH-deficient model. The data suggest that varying the pattern of GH doses administered to children may enhance growth performance without increasing the overall GH dose.insulin-like growth factor; growth hormone deficiency; infradian; insulin-like growth factor-binding protein; acid-labile subunit GROWTH HORMONE (GH) is the major regulator of postnatal body growth (46). Consequently, GH deficiency (GHD) during childhood results in severe growth retardation and, if untreated, marked impairment of adult height. Therefore, children with GHD are offered replacement therapy, and, if given in accordance with the published guidelines of 25-50 g·kg Ϫ1 ·day Ϫ1(31), many achieve an adult height within the normal range. However, this is not always the case; in a group of children with idiopathic GHD, treatment with biosynthetic GH resulted in a mean height standard deviation score of Ϫ0.7, which was 0.45 SD less than the parental target height of Ϫ0.25 (7). GH is also used in the management of other growth problems, for example, in idiopathic short stature and Turner syndrome. Overall, therapy is advantageous, but in these groups there is also considerable variability in the response to GH, and some children remain short even with treatment (33). Thus these studies demonstrate that although GH administration is beneficial for some children, the therapeutic potentia...

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Desensitization of the JAK2/STAT5 GH signaling pathway associated with increased CIS protein content in liver of pregnant mice

Cited by 7 publications

References 77 publications

GH modulates hepatic epidermal growth factor signaling in the mouse

GH modulates hepatic epidermal growth factor signaling in the mouse

Vitamin D3 cannot revert desensitization of growth hormone (GH)-induced STAT5-signaling in GH-overexpressing mice non-calcemic tissues

The effect of different patterns of growth hormone administration on the IGF axis and somatic and skeletal growth of the dwarf rat

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