Role of cytoskeletal proteins in cerebral cavernous malformation signaling pathways: a proteomic analysis

PURPOSE AND DESIGN: The purpose of this review is to provide an overview of the literature linking Ras signaling pathways and leukemia and to discuss the biologic and potential therapeutic implications of these observations. A search of MEDLINE from 1966 to October 1998 was performed. RESULTS: A wealth of data has been published on the role of Ras pathways in cancer. To be biologically active, Ras must move from the cytoplasm to the plasma membrane. Importantly, a posttranslational modification—addition of a farnesyl group to the Ras C-terminal cysteine—is a requisite for membrane localization of Ras. Farnesylation of Ras is catalyzed by an enzyme that is designated farnesyltranferase. Recently, several compounds have been developed that can inhibit farnesylation. Preclinical studies indicate that these molecules can suppress transformation and tumor growth in vitro and in animal models, with little toxicity to normal cells. CONCLUSION: An increasing body of data suggests that disruption of Ras signaling pathways, either directly through mutations or indirectly through other genetic aberrations, is important in the pathogenesis of a wide variety of cancers. Molecules such as farnesyl transferase inhibitors that interfere with the function of Ras may be exploitable in leukemia (as well as in solid tumors) as novel antitumor agents.

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Leptin Upregulates the Expression of β3-Integrin, MMP9, HB-EGF, and IL-1β in Primary Porcine Endometrium Epithelial Cells In Vitro

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17186508 ◽

2020 ◽

Vol 17 (18) ◽

pp. 6508

Author(s):

Hongfang Wang ◽

Jinlian Fu ◽

Aiguo Wang

Keyword(s):

Signaling Pathways ◽

Embryo Implantation ◽

Mapk Signaling ◽

Dependent Manner ◽

Reproductive Disorders ◽

Β3 Integrin ◽

Epithelium Cells ◽

Dose Dependent

Obesity has become a global health problem. Research suggests that leptin, a hormone that responds to fat deposition, may be involved in mammalian reproduction; however, its precise role in embryo implantation is poorly understood. Here, primary porcine endometrium epithelium cells (PEECs) were cultured in vitro and used to evaluate the regulatory role of different leptin levels on β3-integrin, MMP9, HB-EGF, and IL-1β, which are, respectively, involved in four critical steps of embryo implantation. Results showed that only 0.01 nM leptin significantly improved β3-integrin mRNA expression (p < 0.05). MMP9 and HB-EGF mRNA expressions were upregulated by 0.10–10.00 nM leptin (p < 0.05). The IL-1β expression level was only increased by 10.00 nM leptin (p < 0.05). β3-integrin, MMP9, HB-EGF, and IL-1β mRNA and protein have a similar fluctuant response to increased leptin. Leptin’s influence on β3-integrin, MMP9, HB-EGF, and IL-1β disappeared when the JAK2, PI(3)K, or MAPK signaling pathways were blocked, respectively. In conclusion, leptin affected porcine implantation by regulating the expression of β3-integrin, MMP9, HB-EGF, and IL-1β in a dose-dependent manner. The signaling pathways of JAK2, PI(3)K, and MAPK may participate in this regulatory process. These findings will contribute to further understanding the mechanisms of reproductive disorders in obesity.

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Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis

AJP Renal Physiology ◽

10.1152/ajprenal.00113.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. F62-F72 ◽

Cited By ~ 28

Author(s):

Daisuke Son ◽

Ichiro Kojima ◽

Reiko Inagi ◽

Makiko Matsumoto ◽

Toshiro Fujita ◽

...

Keyword(s):

Oxidative Stress ◽

Renal Injury ◽

Proteomic Analysis ◽

Chronic Hypoxia ◽

Kidney Diseases ◽

Pcr Analysis ◽

Tubulointerstitial Injury ◽

Tnf Α

Accumulating evidence suggests a pathogenic role of chronic hypoxia in various kidney diseases. Chronic hypoxia in the kidney was induced by unilateral renal artery stenosis, followed 7 days later by observation of tubulointerstitial injury. Proteomic analysis of the hypoxic kidney found various altered proteins. Increased proteins included lipocortin-5, calgizzarin, ezrin, and transferrin, whereas the decreased proteins were α2u-globulin PGCL1, eukaryotic translation elongation factor 1α2, and Cu/Zn superoxide dismutase (SOD1). Among these proteins, we focused on Cu/Zn-SOD, a crucial antioxidant. Western blot analysis and real-time quantitative PCR analysis confirmed the downregulation of Cu/Zn-SOD in the chronic hypoxic kidney. Furthermore, our laser capture microdissection system showed that the expression of Cu/Zn-SOD was predominant in the tubulointerstitium and was decreased by chronic hypoxia. The tubulointerstitial injury estimated by histology and immunohistochemical markers was ameliorated by tempol, a SOD mimetic. This amelioration was associated with a decrease in levels of the oxidative stress markers 4-hydroxyl-2-nonenal and nitrotyrosine. Our in vitro studies utilizing cultured tubular cells revealed a role of TNF-α in downregulation of Cu/Zn-SOD. Since the administration of anti-TNF-α antibody ameliorated Cu/Zn-SOD suppression, TNF-α seems to be one of the suppressants of Cu/Zn-SOD. In conclusion, our proteomic analysis revealed a decrease in Cu/Zn-SOD, at least partly by TNF-α, in the chronic hypoxic kidney. This study, for the first time, uncovered maladaptive suppression of Cu/Zn-SOD as a mediator of a vicious cycle of oxidative stress and subsequent renal injury induced by chronic hypoxia.

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Proteomic analysis of hypoxia-induced tube breakdown of an in vitro capillary model composed of HUVECs: Potential role of p38-regulated reduction of HSP27

PROTEOMICS ◽

10.1002/pmic.200800055 ◽

2008 ◽

Vol 8 (14) ◽

pp. 2897-2906 ◽

Cited By ~ 11

Author(s):

Ryoji Eguchi ◽

Hirotaka Naitou ◽

Kazuhiro Kunimasa ◽

Rie Ayuzawa ◽

Yoshihiro Fujimori ◽

...

Keyword(s):

Proteomic Analysis ◽

Potential Role ◽

Capillary Model

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Role of long non-coding RNA TP73-AS1 in cancer

Bioscience Reports ◽

10.1042/bsr20192274 ◽

2019 ◽

Vol 39 (10) ◽

Author(s):

Caizhi Chen ◽

Long Shu ◽

Wen Zou

Keyword(s):

Cell Carcinoma ◽

Signaling Pathways ◽

Cell Renal Cell Carcinoma ◽

Aberrant Expression ◽

Diagnosis And Prognosis ◽

Early Diagnosis Of Cancer ◽

Cause Of Deaths

Abstract Cancer incidence rate has increased so much that it is the second leading cause of deaths worldwide after cardiovascular diseases. Sensitive and specific biomarkers are needed for an early diagnosis of cancer and in-time treatment. Recent studies have found that long non-coding RNAs (lncRNAs) participate in cancer tumorigenesis. LncRNA P73 antisense RNA 1T (TP73-AS1), also known as KIAA0495 and p53-dependent apoptosis modulator (PDAM), is located in human chromosomal band 1p36.32 and plays a crucial role in many different carcinomas. This review summarizes current findings on the role of TP73-AS1 and its signaling pathways in various cancers, including glioma, esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), osteosarcoma, gastric cancer (GC), clear cell renal cell carcinoma (ccRCC), breast cancer (BC), bladder cancer, ovarian cancer, cholangiocarcinoma (CCA), lung cancer, and pancreatic cancer. Its aberrant expression generally correlates with clinicopathological characterization of patients. Moreover, TP73-AS1 regulates proliferation, migration, invasion, apoptosis, and chemoresistance cancer mechanisms, both in vivo and in vitro, through different signaling pathways. Therefore, TP73-AS1 may be considered as a marker for diagnosis and prognosis, also as a target for cancer treatment.

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Effect of nerve growth factor on the proliferation in newborn bovine testicular Sertoli cells

Reproduction ◽

10.1530/rep-19-0601 ◽

2020 ◽

Vol 160 (3) ◽

pp. 405-415

Author(s):

Qiaoge Niu ◽

Maosheng Cao ◽

Chenfeng Yuan ◽

Yuwen Huang ◽

Zijiao Zhao ◽

...

Keyword(s):

Cell Proliferation ◽

Nerve Growth Factor ◽

Growth Factor ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Male Reproduction ◽

Nerve Growth ◽

And Function

Nerve growth factor (NGF) has been proved to play important roles in male reproductive physiology, but the molecular mechanisms of NGF action remain unclear. In this study, the effects of NGF on the growth of newborn bovine testicular Sertoli (NBS) cells and the related signaling pathways were investigated. The NBS cells were treated in vitro with NGF (100 ng/mL) for 18 h. The expression levels of cell proliferation related genes, INHBB, and cytoplasmic specialization related gene were determined using real-time PCR and Western blot. The roles of PI3K/AKT and MAPK/ERK pathways in NGF-induced cell proliferation were investigated. It was found that NGF regulates proliferation and function of NBS cells via its receptor NTRK1 by activating the PI3K/ATK and MAPK/ERK signaling pathways. The study will help to further understand the role of NGF in male reproduction and provide new therapeutic targets for reproductive dysfunctions in male animals.

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The Stemness of Human Ovarian Granulosa Cells and the Role of Resveratrol in the Differentiation of MSCs—A Review Based on Cellular and Molecular Knowledge

Cells ◽

10.3390/cells9061418 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1418 ◽

Cited By ~ 1

Author(s):

Malgorzata Jozkowiak ◽

Greg Hutchings ◽

Maurycy Jankowski ◽

Katarzyna Kulcenty ◽

Paul Mozdziak ◽

...

Keyword(s):

Signaling Pathways ◽

Granulosa Cells ◽

Current Knowledge ◽

Biological Activities ◽

Primordial Follicle ◽

Biochemical Processes ◽

Ovarian Granulosa Cells ◽

Physiological Properties

Ovarian Granulosa Cells (GCs) are known to proliferate in the developing follicle and undergo several biochemical processes during folliculogenesis. They represent a multipotent cell population that has been differentiated to neuronal cells, chondrocytes, and osteoblasts in vitro. However, progression and maturation of GCs are accompanied by a reduction in their stemness. In the developing follicle, GCs communicate with the oocyte bidirectionally via gap junctions. Together with neighboring theca cells, they play a crucial role in steroidogenesis, particularly the production of estradiol, as well as progesterone following luteinization. Many signaling pathways are known to be important throughout the follicle development, leading either towards luteinization and release of the oocyte, or follicular atresia and apoptosis. These signaling pathways include cAMP, PI3K, SMAD, Hedgehog (HH), Hippo and Notch, which act together in a complex manner to control the maturation of GCs through regulation of key genes, from the primordial follicle to the luteal phase. Small molecules such as resveratrol, a phytoalexin found in grapes, peanuts and other dietary constituents, may be able to activate/inhibit these signaling pathways and thereby control physiological properties of GCs. This article reviews the current knowledge about granulosa stem cells, the signaling pathways driving their development and maturation, as well as biological activities of resveratrol and its properties as a pro-differentiation agent.

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Abstract 196: Polymorphisms in Cerebral Cavernous Malformation Signaling Pathway Genes Associated With Severity of Cerebral Cavernous Malformation Type 1

Stroke ◽

10.1161/str.46.suppl_1.196 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Hélène Choquet ◽

Ludmila Pawlikowska ◽

Jeffrey Nelson ◽

Charles E McCulloch ◽

Amy Akers ◽

...

Keyword(s):

Disease Severity ◽

Cavernous Malformation ◽

Cerebral Cavernous Malformation ◽

Neurological Deficits ◽

Lesion Count ◽

Large Lesion ◽

Genes Encoding ◽

Dominant Disease ◽

Familial Cerebral Cavernous Malformation

Objective: Familial cerebral cavernous malformation (CCM) is an autosomal dominant disease caused by mutations in CCM1 , CCM2 or CCM3 , and characterized by multiple brain lesions that can lead to intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same mutation can manifest variable symptoms and severity of disease, suggesting the influence of modifiers. As the three CCM proteins form a trimeric complex in vitro and interact with many other proteins, we hypothesized that variants in CCM1-2-3 and in other genes encoding proteins involved in CCM signaling modify disease severity, as manifested by ICH and greater total or large lesion counts. Methods: We analyzed 188 Hispanic CCM1 patients harboring the common Hispanic mutation (CHM, CCM1 Q455X). ICH and lesion counts at enrollment were obtained by clinical assessment and MRI. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 504 variants (MAF≥1%) within +/- 5kb of 42 genes for association with ICH, total and large (≥5 mm in diameter) lesion counts, adjusting for age, gender and family structure. Results: At baseline, 30.3% of CCM1-CHM patients had a history of ICH. Mean total lesion count was 60.1 ± 115.0 (range 0 to 713). Mean large lesion count was 4.9 ± 8.7 (range 0 to 104). Two NTRK1 variants (rs41267423 and rs1800879) as well as SLMAP rs7621574 and PCDHGA1 rs17097189 were significantly associated with ICH ( P ≤0.014). Suggestive associations with ICH ( P ≤0.05) were observed for additional 15 variants in 11 genes. RAP1GAP rs2625408 was associated with both total and large lesion counts ( P ≤0.004) and additional 4 variants in 4 genes were associated with one of these phenotypes. No single variant was associated with both ICH and total or large lesion count; however, different variants in RAP1GAP and KDR genes were associated with all three phenotypes tested. Conclusions: Variants in genes involved in CCM signaling may contribute to variability in CCM1 disease severity. Genotypes that replicate in other cohorts might be useful as predictors in clinical management.

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IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00521.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. H24-H34 ◽

Cited By ~ 9

Author(s):

Dylan J. Wodsedalek ◽

Samantha J. Paddock ◽

Tina C. Wan ◽

John A. Auchampach ◽

Aria Kenarsary ◽

...

Keyword(s):

Cell Cycle ◽

Signaling Pathways ◽

Rna Sequencing ◽

Akt Signaling ◽

Heart Regeneration ◽

Newborn Mice ◽

Neonatal Cardiomyocyte

There is great interest in identifying signaling mechanisms by which cardiomyocytes (CMs) can enter the cell cycle and promote endogenous cardiac repair. We have previously demonstrated that IL-13 stimulated cell cycle activity of neonatal CMs in vitro. However, the signaling events that occur downstream of IL-13 in CMs and the role of IL-13 in CM proliferation and regeneration in vivo have not been explored. Here, we tested the role of IL-13 in promoting neonatal CM cell cycle activity and heart regeneration in vivo and investigated the signaling pathway(s) downstream of IL-13 specifically in CMs. Compared with control, CMs from neonatal IL-13 knockout (IL-13−/−) mice showed decreased proliferative markers and coincident upregulation of the hypertrophic marker brain natriuretic peptide ( Nppb) and increased CM nuclear size. After apical resection in anesthetized newborn mice, heart regeneration was significantly impaired in IL-13−/− mice compared with wild-type mice. Administration of recombinant IL-13 reversed these phenotypes by increasing CM proliferation markers and decreasing Nppb expression. RNA sequencing on primary neonatal CMs treated with IL-13 revealed activation of gene networks regulated by ERK1/2 and Akt. Western blot confirmed strong phosphorylation of ERK1/2 and Akt in both neonatal and adult cultured CMs in response to IL-13. Our data demonstrated a role for endogenous IL-13 in neonatal CM cell cycle and heart regeneration. ERK1/2 and Akt signaling are important pathways known to promote CM proliferation and protect against apoptosis, respectively; thus, targeting IL-13 transmembrane receptor signaling or administering recombinant IL-13 may be therapeutic approaches for activating proregenerative and survival pathways in the heart. NEW & NOTEWORTHY Here, we demonstrate, for the first time, that IL-13 is involved in neonatal cardiomyocyte cell cycle activity and heart regeneration in vivo. Prior work has shown that IL-13 promotes cardiomyocyte cell cycle activity in vitro; however, the signaling pathways were unknown. We used RNA sequencing to identify the signaling pathways activated downstream of IL-13 in cardiomyocytes and found that ERK1/2 and Akt signaling was activated in response to IL-13.

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