GNAI2 Promotes Proliferation and Decreases Apoptosis in Rabbit Melanocytes.
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ABSTRACT:
SUBMITTER: Hu S
PROVIDER: S-EPMC8392598 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundVitiligo is an acquired chronic and recurrent skin disease that causes a depigmentation disorder, resulting in selective destruction of melanocytes (MC). However, the mechanism that leads to melanocyte dysfunction and death remains unclear.MethodsWe performed RNA sequencing, immunohistochemistry, and immunoblotting to characterize the patterns of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway activation in vitiligo. We also cocultured primary melanocytes with mesenchymal stem cells (MSCs) in a Transwell system to explore how MSCs inhibit the PTEN/PI3K/AKT pathway in melanocytes.ResultsWe identified that vitiligo normal-lesional junction skin presented with high expression of PTEN, which led to the inhibition of AKT phosphorylation (p-AKT) at S-473. Furthermore, PTEN overexpression led to oxidative stress-induced apoptosis in melanocytes. Coculturing with MSCs enhanced the cell proliferation of human melanocytes and repressed PTEN expression, which inhibited oxidative stress-induced apoptosis.ConclusionWe report that vitiligo patients present with high PTEN expression, which may play a role in the impairment of melanocytes. Furthermore, our study provides evidence that MSCs target the PTEN/PI3K/AKT pathway to regulate cell proliferation and apoptosis in human melanocytes, indicating that MSCs may serve as a promising therapy for vitiligo.
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Project description:BackgroundMelanocytes play an extremely important role in the process of skin and coat colors in mammals which is regulated by melanin-related genes. Previous studies have demonstrated that KIT is implicated in the process of determining the color of the coat in Rex rabbits. However, the effect of KIT on the proliferation and apoptosis of melanocytes and melanogenesis has not been clarified.MethodsThe mRNA and protein expression levels of KIT were quantified in different coat colored rabbits by qRT-PCR and a Wes assay. To identify whether KIT functions by regulating of melanogenesis, KIT overexpression and knockdown was conducted in melanocytes, and KIT mRNA expression and melanin-related genes TYR, MITF, PMEL and DCT were quantified by qRT-PCR. To further confirm whether KIT influences melanogenesis in melanocytes, melanin content was quantified using NaOH lysis after overexpression and knockdown of KIT. Melanocyte proliferation was estimated using a CCK-8 assay at 0, 24, 48 and 72 h after transfection, and the rate of apoptosis of melanocytes was measured by fluorescence-activated cell sorting.ResultsKITmRNA and protein expression levels were significantly different in the skin of Rex rabbits with different color coats (P < 0.05), the greatest levels observed in those with black skin. The mRNA expression levels of KIT significantly affected the mRNA expression of the pigmentation-related genes TYR, MITF, PMEL and DCT (P < 0.01). Melanin content was evidently regulated by the change in expression patterns of KIT (P < 0.01). In addition, KIT clearly promoted melanocyte proliferation, but inhibited apoptosis.ConclusionsOur results reveal that KIT is a critical gene in the regulation of melanogenesis, controlling proliferation and apoptosis in melanocytes, providing additional evidence for the mechanism of pigmentation of animal fur.
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Project description:We have previously shown that estrogens binding to estrogen receptor (ER) ? increase proliferation of Leydig tumor cells. Estrogens can also bind to G protein-coupled ER (GPER) and activation of this receptor can either increase or decrease cell proliferation of several tumor types. The aim of this study was to investigate GPER expression in R2C rat tumor Leydig cells, evaluate effects of its activation on Leydig tumor cell proliferation and define the molecular mechanisms triggered in response to its activation. R2C cells express GPER and its activation, using the specific ligand G-1, is associated with decreased cell proliferation and initiation of apoptosis. Apoptosis after G-1 treatment was asserted by appearance of DNA condensation and fragmentation, decrease in Bcl-2 and increase in Bax expression, cytochrome c release, caspase and poly (ADP-ribose) polymerase-1 (PARP-1) activation. These effects were dependent on GPER activation because after silencing of the gene, using a specific small interfering RNA, cyt c release, PARP-1 activation and decrease in cell proliferation were abrogated. These events required a rapid, however, sustained extracellular regulated kinase 1/2 activation. G-1 was able to decrease the growth of R2C xenograft tumors in CD1 nude mice while increasing the number of apoptotic cells. In addition, in vivo administration of G-1 to male CD1 mice did not cause any alteration in testicular morphology, while cisplatin, the cytotoxic drug currently used for the therapy of Leydig tumors, severely damaged testicular structure, an event associated with infertility in cisplatin-treated patients. These observations indicate that GPER targeting for the therapy of Leydig cell tumor may represent a good alternative to cisplatin to preserve fertility in Leydig tumor patients.
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Project description:We show here that keratinocytic nuclear receptor retinoid X receptor-? (RXR?) regulates mouse keratinocyte and melanocyte homeostasis following acute UVR. Keratinocytic RXR? has a protective role in UVR-induced keratinocyte and melanocyte proliferation/differentiation, oxidative stress-mediated DNA damage, and cellular apoptosis. We discovered that keratinocytic RXR?, in a cell-autonomous manner, regulates mitogenic growth responses in skin epidermis through secretion of heparin-binding EGF-like growth factor, GM-CSF, IL-1?, and cyclooxygenase-2 and activation of mitogen-activated protein kinase pathways. We identified altered expression of several keratinocyte-derived mitogenic paracrine growth factors such as endothelin 1, hepatocyte growth factor, ?-melanocyte stimulating hormone, stem cell factor, and fibroblast growth factor-2 in skin of mice lacking RXR? in epidermal keratinocytes (RXR?(ep-/-) mice), which in a non-cell-autonomous manner modulated melanocyte proliferation and activation after UVR. RXR?(ep-/-) mice represent a unique animal model in which UVR induces melanocyte proliferation/activation in both epidermis and dermis. Considered together, the results of our study suggest that RXR antagonists, together with inhibitors of cell proliferation, can be effective in preventing solar UVR-induced photocarcinogenesis.
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Project description:Background:Abnormal expression of protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) is closely associated with multiple types of cancers. In the present study, we examined the roles of PKMYT1 in gastric cancer (GC) progression. Methods:We examined the expression status of PKMYT1 in GC tissues and cell lines. Meanwhile, short hairpin RNA (shRNA) was used to inhibit the endogenous expression of PKMYT1 in GC cells. Then we analyzed the effect of PKMYT1 on the malignant biological behavior of GC cells by in vitro and in vivo experiments. Results:The findings showed high PKMYT1 expressions in GC tissues as well as a positive correlation between PKMYT1 expression and prognosis of patients with GC. Additional findings also revealed that PKMYT1 silencing significantly enhanced apoptosis and inhibited GC cell proliferation. In vivo, the silence of PKMYT1 inhibits tumor growth. Further analysis showed that the increase in PKMYT1 expressions led to malignant biological behavior through activation of the MAPK signaling pathway. Conclusion:Our data suggested that PKMYT1 promotes cell proliferation and apoptosis resistance in GC cells by activating the MAPK signaling pathway, making it a potential therapeutic target for GC.
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Project description:Glioma is the most general primary and lethal intracranial malignant tumor. Pterostilbene (PTE), an analog of stilbene and resveratrol, has attracted attention in recent years due to its significant antitumor activity in multiple solid tumors; however, its effect on drug-resistant glioma cells and the underlying mechanism have not yet been reported. In this study, we found that pterostilbene inhibited proliferation, induced intrinsic mitochondria-mediated apoptosis and caused S phase arrest, inhibited migration and excessive invasion in glioma cells. Pretreatment with the pan-caspase-inhibitor Z-VAD-FMK attenuated the PTE-induced apoptosis of glioma cells. Moreover, PTE significantly increased the production of reactive oxygen species (ROS) and reduce the mitochondrial membrane potential (MMP). Inhibition of ROS with N-acetyl-L-cysteine not only rescued PTE-induced reduction of cellular viability but also prevented glioma cell apoptosis. We also discovered ERK 1/2 and JNK signaling pathways were activated by PTE and contributed to induce glioma cell apoptosis. In addition, specific inhibitors of ERK 1/2 and JNK attenuated PTE-induced apoptosis. Besides, PTE significantly reduced tumor volume and prolonged median survival of tumor-bearing rats in vivo. In summary, the results of this study indicate that the anti-tumor effect of PTE on glioma cells may provide a new treatment option for glioma patients.
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Project description:Galanin is a neuropeptide with a wide range of effects in the nervous and endocrine systems, mediated through three G protein-coupled receptor subtypes (GalR1-3). Interestingly, galanin and its receptors are also expressed in certain tumors. Here we studied the effects of galanin in rat pheochromocytoma (PC12) cells stably transfected with GFP-tagged GalR2. Galanin at 100 nM inhibited cell proliferation in both nontransfected and transfected cells. Conversly, both galanin and the GalR2(R3)-agonist AR-M1896 induced caspase-dependent apoptotic cell death only in GalR2-transfected cells. Western-blot analyses of downstream mediators of the G(q/11)-type G protein showed down-regulation of pAkt and pBad in galanin-exposed transfected cells. Also, the specific PI3 kinase inhibitor LY-294002 increased the level of pBad and decreased activation of caspases. In addition, p21(cip1) levels were up-regulated in galanin-exposed PC12 cells and down-regulated in galanin-exposed GalR2-transfected cells. In agreement, FACS analyses of galanin exposed cells showed occurrence of cell cycle arrest in PC12 cells and cell death in transfected cells. Finally, as shown with real-time PCR, galanin and its receptors were expressed at very high levels in human pheochromocytoma tissues as compared with normal adrenal medulla. These findings point to GalR2 as a possible target for therapeuthic interventions in pheochromocytoma.
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Project description:This study aimed to investigate the effect of the long non-coding RNA (lncRNA) Dlx6os1 inhibitor on cell proliferation, apoptosis and fibrosis in mouse mesangial cells (MMCs) under high glucose (HG) conditions. SV40 MES13 cells were cultured under 30 mmol/L glucose (HG group), 5.6 mmol/L glucose (normal glucose group, NG group) and 5.6 mmol/L glucose plus 24.4 mmol/L 3-O-methyl-D-glucose (osmotic control group, OC group), and expressions of lncRNA Dlx6os1, Gm13730, Rdh9, Chrm2 and Bex1 were determined by qPCR. NC-inhibitor plasmids and lncRNA Dlx6os1 inhibitor plasmids were transfected into SV40 MES13 cells cultured under HG conditions, and cell proliferation (at 0 h, 24 h, 48 h and 72 h), and the apoptosis rate (at 72 h), proteins and mRNAs expressions for proliferation and fibrosis markers (at 72 h) were detected by CCK-8, AV-PI, Western blot and qPCR assays, respectively. LncRNA Dlx6os1 was increased in the HG group compared with the OC and NG groups, while no difference of lncRNA Gm13730, Rdh9, Chrm2 or Bex1 was discovered among the three groups. The lncRNA Dlx6os1 inhibitor decreased cell proliferation at 24 h, 48 h and 72 h post plasmids transfection by the CCK-8 assay and reduced the expressions of Cyclin D1 and proliferating cell nuclear antigen (PCNA) mRNA and protein expressions compared with the NC-inhibitor. The cell apoptosis rate at 72 h increased compared with the NC-inhibitor. In addition, protein and mRNA expressions of markers for cell fibrosis (fibronectin and collagen I) were all decreased in the lncRNA Dlx6os1-inhibitor group compared to the NC-inhibitor group. In conclusion, inhibition of lncRNA Dlx6os1 decreases cell proliferation and fibrosis and increases cell apoptosis in diabetic nephropathy.
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Project description:FOXL2 is a transcription factor that is essential for ovarian function and maintenance, the germline mutations of which give rise to the blepharophimosis ptosis epicanthus inversus syndrome (BPES), often associated with premature ovarian failure. Recently, its mutations have been found in ovarian granulosa cell tumors (OGCTs). In this study, we measured the expression of FOXL2 in cervical cancer by immunohistochemistry and its mRNA level in cervical cancer cell lines Hela and Siha by RT-PCR. Then we overexpressed FOXL2 in Hela cells and silenced it in Siha cells by plasmid transfection and verified using western blotting. When FOXL2 was overexpressed or silenced, cells proliferation and apoptosis were determined by Brdu assay and Annexin V/PI detection kit, respectively. In addition, we investigated the effects of FOXL2 on the adhesion and invasion of Hela and Siha cells. Finally, we analyzed the influences of FOXL2 on Ki67, PCNA and FasL by flow cytometry. The results showed that FOXL2 was highly expressed in cervical squamous cancer. Overexpressing FOXL2 suppressed Hela proliferation and facilitated its apoptosis. Silencing FOXL2 enhanced Siha proliferation and inhibited its apoptosis. Meanwhile, silencing FOXL2 promoted Siha invasion, but it had no effect on cells adhesion. In addition, overexpressing FOXL2 decreased the expression of Ki67 in Hela and Siha cells. Therefore, our results suggested that FOXL2 restrained cells proliferation and enhanced cells apoptosis mainly through decreasing Ki67 expression.
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