SP1 and RARα regulate AGAP2 expression in cancer

Doush, Yegor; Surani, Arif A.; Navarro‐Corcuera, Amaia; McArdle, Stephanie E.B.; Billett, E. Ellen; Montiel-Duarte, Cristina

doi:10.1038/s41598-018-36888-x

Cited by 13 publications

(16 citation statements)

References 50 publications

(55 reference statements)

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“…Additionally, the promoter region of AGAP2 has also been found to be hypermethylated in GDM-born offspring [40], which is similar to our findings in RES male offspring [36]. Given the key role of HOX genes in cell differentiation, function, and cancer [41] as well as AGAP2 as a proto-oncogene [42], additional work needs to be conducted to determine if changes in the expression of these genes could alter the histology and function of the pancreas tissue.…”

Section: Discussionsupporting

confidence: 82%

Maternal Under- and Over-Nutrition during Gestation Causes Islet Hypertrophy and Sex-Specific Changes to Pancreas DNA Methylation in Fetal Sheep

Peterson

Gauvin

Pillai

et al. 2021

Animals

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The mechanisms by which fetal programming predisposes offspring to reduced β-cell function later in life are poorly understood. We hypothesized that maternal under- and over-nutrition during gestation would negatively affect offspring pancreas development and alter DNA methylation patterns. Pregnant ewes (n = 78) were fed 100, 60, or 140% of NRC requirements beginning at d 30.2 ± 0.2 of gestation. The fetuses are referred to as CON, RES, and OVER, respectively. Fetal pancreas tissue was collected at d 90 or 135 of gestation or within 24 h of birth. Tissue was preserved for histological (n = 8 to 9 offspring per treatment per time point) and DNA methylation analyses (n = 3 to 4 fetuses per treatment per sex). At d 135, OVER exhibited an increased islet size, reduced islet number, and greater insulin positive area compared with CON (p ≤ 0.03). An increased islet size was also observed at d 135 in RES (p ≤ 0.03) compared with CON. Cellular proliferation was reduced at birth in OVER vs. CON (p = 0.01). In the RES vs. CON females, 62% of the differentially methylated regions (DMRs) were hypomethylated (p ≤ 0.001). In the RES vs. CON males, 93% of the DMRs were hypermethylated (p ≤ 0.001). In OVER, 66 and 80% of the DMRs were hypermethylated in the female and male offspring compared with CON (p ≤ 0.001). In conclusion, changes to maternal diet during pregnancy affects the islet hypertrophy and cellular proliferation of the offspring at early post-natal time points. Additionally, changes in DNA methylation patterns appear to be in a diet-specific and sex-dependent manner.

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Section: Discussionsupporting

confidence: 82%

Maternal Under- and Over-Nutrition during Gestation Causes Islet Hypertrophy and Sex-Specific Changes to Pancreas DNA Methylation in Fetal Sheep

Peterson

Gauvin

Pillai

et al. 2021

Animals

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“…The transcription factor Sp1 regulates the transcription of several genes 43 – 45 . Takagi et al ., used primary human keratinocytes to analyze the structure of the human ATP2A2 promoter.…”

Section: Discussionmentioning

confidence: 99%

Luteolin modulates SERCA2a via Sp1 upregulation to attenuate myocardial ischemia/reperfusion injury in mice

Zhang

Zhu

et al. 2020

Sci Rep

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The sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) is responsible for calcium transport during excitation–contraction coupling and is essential for maintaining myocardial systolic/diastolic function and intracellular Ca2+ levels. Therefore, it is important to investigate mechanisms whereby luteolin modulates SERCA2a expression to attenuate myocardial ischemia/reperfusion injury. C57BL/6j mice were randomly divided into eight groups. The expression and activity of SERCA2a was measured to assess interactions between the SERCA2a promoter and the Sp1 transcription factor, and the regulatory effects of luteolin. We used serum LDH release, serum cardiac troponin I level, hemodynamic data, myocardial infarction size and apoptosis-related indices to measure SERCA2a cardio-protective effects of luteolin pretreatment. Sp1 binding to SERCA2a promoter under ischemia/reperfusion conditions in the presence or absence of luteolin was analyzed by chromatin immunoprecipitation. Our experimental results indicated that during myocardial ischemia/reperfusion injury, luteolin pretreatment upregulated the expression levels of SERCA2a and Sp1. Sp1 overexpression enhanced the expression of SERCA2a at the transcriptional level. Luteolin pretreatment reversed the expression of SERCA2a through the increased expression of Sp1. Moreover, we demonstrated that luteolin pretreatment appeared to exert myocardial protective effects by upregulating the transcriptional activity of SERCA2a, via Sp1. In conclusion, during myocardial ischemia/reperfusion, Sp1 appeared to downregulate the expression of SERCA2a. Luteolin pretreatment was shown to improve SERCA2a expression via the upregulation of Sp1 to attenuate myocardial ischemia/reperfusion injury.

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“…Reporter assays have identified the nucleotides -246/+36 in AGAP2 DNA sequence containing the minimal AGAP2 promoter region involved in AGAP2 expression in both chronic myeloid leukemia and prostate cancer human cell lines. Specificity protein 1 (SP1) transcription factor has been found to be bound to this fragment and to be required for AGAP2 expression in these tumoral cell lines [25]. Furthermore, the AGAP2 promoter fragment -475/-246 contains a functional direct repeat of two motifs (G/AGTTCA) separated by 5 bp (DR5) binding site with a retinoic acid response element (RARE), which seems to be functional as the addition of all-trans retinoic acid (ATRA) induced AGAP2 promoter activity and increased AGAP2 expression.…”

Section: Regulation Of Agap2 Expression and Activitymentioning

confidence: 99%

“…Chromatin immunoprecipitation assays confirmed that the nuclear receptors RARα (retinoic acid receptor α) and RXRα (retinoid X receptor α) and the lysine acetyl transferase acetyl transferase P300/CBP-associated factor (PCAF) were present at the promoter under conditions of AGAP2 expression in prostate cancer cells. And it was proposed that ATRA might lead to the recruitment of PCAF and perhaps increased SP1 binding to AGAP2 promoter, thereby leading to increased AGAP2 levels in cancer cells [25].…”

Section: Regulation Of Agap2 Expression and Activitymentioning

confidence: 99%

“…AGAP2 (Arf GAP with GTP-binding protein-like domain, Ankyrin repeat and pleckstrin homology (PH) domain 2) expression and activity are regulated by phosphorylation. Cdk5 (cyclin dependent kinase 5) phosphorylates AGAP2 at Serine (S)-279 which is located in its G domain [26]; AMPK (AMP-activated protein kinase), the main energy sensor, phosphorylates AGAP2 on Ser-351 and Ser-377 which are located on its PH domain, under cellular energy stress conditions [25]; AKT (protein kinase B) phosphorylates AGAP2 at S472 [27] and S629 [28] which are in PH and GAP domains, respectively; Fyn phosphorylates AGAP2 at tyrosine (Y) 682 and Y774 in GAP domain [29]. Green arrows indicate process induced by AGAP2 phosphorylated in a precise residue.…”

Section: Regulation Of Agap2 Expression and Activitymentioning

confidence: 99%

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AGAP2: Modulating TGFβ1-Signaling in the Regulation of Liver Fibrosis

Navarro‐Corcuera

Ansorena

Montiel-Duarte

et al. 2020

IJMS

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AGAP2 (Arf GAP with GTP-binding protein-like domain, Ankyrin repeat and PH domain 2) isoform 2 is a protein that belongs to the Arf GAP (GTPase activating protein) protein family. These proteins act as GTPase switches for Arfs, which are Ras superfamily members, being therefore involved in signaling regulation. Arf GAP proteins have been shown to participate in several cellular functions including membrane trafficking and actin cytoskeleton remodeling. AGAP2 is a multi-tasking Arf GAP that also presents GTPase activity and is involved in several signaling pathways related with apoptosis, cell survival, migration, and receptor trafficking. The increase of AGAP2 levels is associated with pathologies as cancer and fibrosis. Transforming growth factor beta-1 (TGF-β1) is the most potent pro-fibrotic cytokine identified to date, currently accepted as the principal mediator of the fibrotic response in liver, lung, and kidney. Recent literature has described that the expression of AGAP2 modulates some of the pro-fibrotic effects described for TGF-β1 in the liver. The present review is focused on the interrelated molecular effects between AGAP2 and TGFβ1 expression, presenting AGAP2 as a new player in the signaling of this pro-fibrotic cytokine, thereby contributing to the progression of hepatic fibrosis.

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SP1 and RARα regulate AGAP2 expression in cancer

Cited by 13 publications

References 50 publications

Maternal Under- and Over-Nutrition during Gestation Causes Islet Hypertrophy and Sex-Specific Changes to Pancreas DNA Methylation in Fetal Sheep

Maternal Under- and Over-Nutrition during Gestation Causes Islet Hypertrophy and Sex-Specific Changes to Pancreas DNA Methylation in Fetal Sheep

Luteolin modulates SERCA2a via Sp1 upregulation to attenuate myocardial ischemia/reperfusion injury in mice

AGAP2: Modulating TGFβ1-Signaling in the Regulation of Liver Fibrosis

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