GH/STAT5 signaling during the growth period in livers of mice overexpressing GH

Martínez, Carolina; Piazza, Veronica; Díaz, María Alejandra; Boparai, Ravneet K.; Arum, Oge; Ramírez, María Cecilia; González, Lorena; Becú-Villalobos, Damasia; Bartke, Andrzej; Turyn, Daniel; Miquet, Johanna G.; Sotelo, Ana I.

doi:10.1530/jme-14-0262

Cited by 10 publications

(23 citation statements)

References 71 publications

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“…Animals of representative ages were chosen: 2 weeks (2w), when animals of both genotypes exhibit similar body size; 4 weeks (4w), when faster growing transgenic mice start to exhibit different body proportions than normal siblings; and nine weeks (9w), young adults used as reference, which have a clear enlargement of body size. 13 Non-transgenic siblings were used as controls. The mice were housed 3 to 5 per cage in a room with controlled light (12 h light per day) and temperature (22 § 2 C); they had free access to food (Rodent Laboratory Chow 5001; not autoclaved; 23.4% protein, 4.5% fat, 5.8% crude fiber; LabDiet, PMI Feeds, Inc.) and tap water.…”

Section: Animalsmentioning

confidence: 99%

“…5 MEK/ERK and PI3K/Akt pathways are engaged in protein synthesis required for cellular growth and promote cellular proliferation and differentiation. 10 Transgenic mice overexpressing growth hormone present high circulating GH levels since birth, despite of which, they exhibit accelerated growth only after the third week of postnatal life [11][12][13] and achieve greater adult body size than control mice. [14][15][16][17] We have recently reported that STAT5 signaling is enhanced in the liver of growing GH-transgenic mice but not in adult animals, supporting a central role of this pathway in the promotion of body growth during the postnatal growth period.…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16][17] We have recently reported that STAT5 signaling is enhanced in the liver of growing GH-transgenic mice but not in adult animals, supporting a central role of this pathway in the promotion of body growth during the postnatal growth period. 13,17,18 Enhanced body growth of these GH-overexpressing mice is concomitant with organomegaly, which is particularly important in the liver. 16,17,[19][20][21][22][23] Hepatomegaly emerges as a consequence of the hypertrophy and hyperplasia of the hepatocytes, with the frequent progression to liver tumors at advanced ages.…”

Section: Introductionmentioning

confidence: 99%

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Mitogenic signaling pathways in the liver of growth hormone (GH)-overexpressing mice during the growth period

et al. 2016

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Growth hormone (GH) is a pleiotropic hormone that triggers STATs, ERK1/2 and Akt signaling, related to cell growth and proliferation. Transgenic mice overexpressing GH present increased body size, with a disproportionate liver enlargement due to hypertrophy and hyperplasia of the hepatocytes. We had described enhanced mitogenic signaling in liver of young adult transgenic mice. We now evaluate the activation of these signaling cascades during the growth period and relate them to the morphological alterations found. Signaling mediators, cell cycle regulators and transcription factors involved in cellular growth in the liver of GH-overexpressing growing mice were assessed by immunoblotting, RT-qPCR and immunohistochemistry. Hepatocyte enlargement can be seen as early as 2-weeks of age in GH-overexpressing animals, although it is more pronounced in young adults. Levels of cell cycle mediators PCNA and cyclin D1, and transcription factor c-Jun increase with age in transgenic mice with no changes in normal mice, whereas c-Myc levels are higher in 2-week-old transgenic animals and cyclin E levels decline with age for both genotypes. STAT3, Akt and GSK3 present higher activation in the adult transgenic mice than in the growing animals, while for c-Src and mTOR, phosphorylation in GH-overexpressing mice is higher than in control siblings at 4 and 9 weeks of age. No significant changes are observed for ERK1/2, neither by age or genotype. Thus, the majority of the mitogenic signaling pathways are gradually up-regulated in the liver of GH-transgenic mice, giving rise to the hepatic morphological changes these mice exhibit.

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Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitogenic signaling pathways in the liver of growth hormone (GH)-overexpressing mice during the growth period

et al. 2016

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“…The breeding system followed in order to obtain transgenic mice, as well as animal housing and feeding conditions, were previously described [18,19]. Mice were killed by cervical dislocation under isofluorane anesthesia, and skeletal muscle from the hind limbs was removed and stored at −70 °C until use.…”

Section: Methodsmentioning

confidence: 99%

Analysis of Different Approaches for the Selection of Reference Genes in RT-qPCR Experiments: A Case Study in Skeletal Muscle of Growing Mice

Piazza

Bartke

Miquet

et al. 2017

IJMS

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The reliability of reverse transcription-quantitative PCR (RT-qPCR) results in gene expression studies depends on the approaches used to account for non-biological variations. In order to find a proper normalization strategy for the study of genes related to growth hormone signaling in skeletal muscle of growing mice, nine unrelated genes were evaluated as internal controls. According to the most used algorithms–geNorm, the Comparative ΔCq method, NormFinder and BestKeeper–GSK3B, YWHAZ, RPL13A and RN18S were found as the most stable. However, the relative expression levels of eight of the potential reference genes assessed decreased with age in cDNA samples obtained from the same amount of total RNA. In a different approach to analyze this apparent discrepancy, experiments were performed with cDNA obtained from equal amounts of purified mRNA. Since the decline was still observed, the hypothesis of an age-related change in mRNA to total RNA ratio that could account for the systematic decrease was rejected. Differences among experimental groups could be due to a substantial increase with age in highly expressed mRNAs, which would bias the quantitation of the remaining genes. Consequently, those reference genes reflecting this dilution effect, which would have been discarded considering their variable relative expression levels, arose as suitable internal controls.

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“…Consistent with the diminished phosphorylation of Stat5b, its nuclear localisation was also reduced in Ankhd1-deficient polycystic kidneys (fig 5b). Furthermore, the induction of Insulin growth factor 1 (Igf1), CIS and Suppressor of cytokine signalling 3 (SOCS3), genes transcriptionally activated by Stat5 22 , were reduced in Ankhd1 -/+ compared with Ankhd1 +/+ control kidneys (Figure 5c). These results indicate that Ankhd1 positively regulates the STAT5 activity in ADPKD.…”

Section: Ankhd1 Silencing Reduces Proliferation Potential In Human Pamentioning

confidence: 99%

Ankhd1enhances polycystic kidney disease development via promoting proliferation and fibrosis

Patera

Hautbergue

Wilson

et al. 2020

Preprint

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disorder resulting in 10% of patients with renal failure. The molecular events responsible for the relentless growth of cysts are not defined. Thus, identification of novel drivers of ADPKD may lead to new therapies. Ankyrin Repeat and Single KH domain-1 (ANKHD1) controls cancer cell proliferation, yet its role in ADPKD is unexplored. Here, we present the first data that identify ANKHD1 as a driver of proliferative growth in cellular and mouse models of ADPKD. Using the first Ankhd1-deficient mice, we demonstrate that Ankhd1 heterozygosity potently reduces cystic growth and fibrosis, in a genetically orthologous mouse model of ADPKD. We performed transcriptome-wide profiling of patient-derived ADPKD cells with and without ANKHD1 siRNA silencing, revealing a major role for ANKHD1 in the control of cell proliferation and matrix remodelling. We validated the role of ANKHD1 in enhancing proliferation in patient-derived cells. Mechanistically ANKHD1 promotes STAT5 signalling in ADPKD mice. Hence, ANKHD1 is a novel driver of ADPKD, and its inhibition may be of therapeutic benefit.

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GH/STAT5 signaling during the growth period in livers of mice overexpressing GH

Cited by 10 publications

References 71 publications

Mitogenic signaling pathways in the liver of growth hormone (GH)-overexpressing mice during the growth period

Mitogenic signaling pathways in the liver of growth hormone (GH)-overexpressing mice during the growth period

Analysis of Different Approaches for the Selection of Reference Genes in RT-qPCR Experiments: A Case Study in Skeletal Muscle of Growing Mice

Ankhd1enhances polycystic kidney disease development via promoting proliferation and fibrosis

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