SAD-A Promotes Pancreatic ß-Cell Proliferation by Regulating ß-Cell Cycle as a Downstream Target of mTORC1 Signaling

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 53-OR
Author(s):  
JIA NIE ◽  
NICOLAS MUSI ◽  
YUGUANG SHI
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Downstream Target ◽  
Mtorc1 Signaling

scholarly journals Human Chorionic Gonadotropin Stimulates Theca-Interstitial Cell Proliferation and Cell Cycle Regulatory Proteins by a cAMP-Dependent Activation of AKT/mTORC1 Signaling Pathway

2010 ◽  
Vol 24 (9) ◽  
pp. 1782-1793 ◽  
Author(s):  
Murugesan Palaniappan ◽  
K.M.J. Menon
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Chorionic Gonadotropin ◽  
Proliferating Cell Nuclear Antigen ◽  
Regulatory Proteins ◽  
Cyclin D3 ◽  
Nuclear Antigen ◽  
Mtorc1 Signaling ◽  
Cell Cycle Regulatory Proteins ◽  
Proliferating Cell

Abstract In addition to playing a cardinal role in androgen production, LH also regulates growth and proliferation of theca-interstitial (T-I) cells. Here, we show for the first time that LH/human chorionic gonadotropin (hCG) regulates T-I cell proliferation via the mammalian target of rapamycin complex 1 (mTORC1) signaling network. LH/hCG treatment showed a time-dependent stimulation of T-I cell proliferation and phosphorylation of protein kinase B (AKT), ERK1/2, and ribosomal protein (rp)S6 kinase 1 (S6K1), and its downstream effector, rpS6. Pharmacological inhibition of ERK1/2 signaling did not block the hCG-induced phosphorylation of tuberin, the upstream regulator of mTORC1 or S6K1, the downstream target of mTORC1. However, inhibition of AKT signaling completely blocked the hCG response. Furthermore, the AKT-specific inhibitor abolished forskolin (FSK)-stimulated phosphorylation of AKT, tuberin, S6K1, and rpS6. Human CG and FSK-mediated phosphorylation of AKT and downstream targets of mTORC1 were attenuated by inhibition of adenylyl cyclase. Pharmacologic targeting of mTORC1 with rapamycin also abrogated hCG or FSK-induced phosphorylation of S6K1, rpS6, and eukaryotic initiation factor 4E binding protein 1. In addition, hCG or FSK-mediated up-regulation of the cell cycle regulatory proteins cyclin-dependent kinase 4, cyclin D3, and proliferating cell nuclear antigen was blocked by rapamycin. These results were further confirmed by demonstrating that knockdown of mTORC1 using small interfering RNA abolished hCG-mediated increases in cell proliferation and the expression of cyclin D3 and proliferating cell nuclear antigen. Taken together, the present studies show a novel intracellular signaling pathway for T-I cell proliferation involving LH/hCG-mediated activation of the AKT/mTORC1 signaling cascade.

scholarly journals circRPS16 Promotes Proliferation and Invasion of Hepatocellular Carcinoma by Sponging miR-876-5p to Upregulate SPINK1

2021 ◽  
Vol 11 ◽  
Author(s):  
Shuwen Lin ◽  
Ye Lin ◽  
Zhongshi Wu ◽  
Wuzheng Xia ◽  
Chenglong Miao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Luciferase Reporter ◽  
Downstream Target ◽  
Proliferation And Invasion

The roles of serine protease inhibitor Kazal type 1 (SPINK1) in multiple types of cancers have been significantly documented. However, its specific roles in hepatocellular carcinoma (HCC) remain to be investigated. This study found that SPINK1 is upregulated in HCC and its upregulation correlates with poor prognosis. Besides, functional assays revealed that SPINK1 promotes cell proliferation, cell cycle, and invasion in vitro. Through bioinformatics analysis, we speculate that circRPS16 regulates SPINK1 expression by sponging miR-876-5p. This was further verified by the dual-luciferase reporter and fluorescent in situ hybridization (FISH) assays. Subsequently, rescue assays verified that circRPS16 promotes cell proliferation, cell cycle, and invasion through miR-876-5p. Importantly, silencing circRPS16 inhibited tumor growth by downregulating SPINK1 expression in vivo. Collectively, our results confirm that SPINK1 is a downstream target of circRPS16. Besides, circRPS16 and SPINK1 are oncogenic factors in HCC progression; they provide novel diagnostic and therapeutic targets for HCC patients.

scholarly journals LncRNA MNX1-AS1 promotes ovarian cancer process via targeting the miR-744-5p/SOX12 axis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yang Shen ◽  
Mengmeng Lv ◽  
Yichen Fang ◽  
Jin Lu ◽  
Yuzhong Wu
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Promoting Effect ◽  
Downstream Target ◽  
Tumor Tissues

Abstract Purpose Ovarian cancer (OC) is the most common malignancy in women with high mortality. Increasing studies have revealed that long non-coding RNA (lncRNA) MNX1-AS1 has a promoting effect on various cancers. However, the mechanisms of MNX1-AS1 in OC are still unclear. Therefore, this study focused on exploring the mechanisms of MNX1-AS1 in OC. Materials and methods The expression of SOX12 at the protein level was detected by western blot. Cell proliferation was detected by CCK8 assay and colony formation assay. Cell cycle and cell apoptosis were detected by flow cytometry. Wound-healing assay, transwell assay and western blot were used to detect the ability of cell migration and invasion. The target binding was confirmed through the luciferase reporter assay. Results The expression of MNX1-AS1 was increased in OC tumor tissues and cells. Elevated MNX1-AS1 expression is associated with advanced stage and lower overall survival rate. Knockdown of MNX1-AS1 inhibited cell proliferation, migration and invasion, blocked cell cycle, and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. MNX1-AS1 was competitively binding with miR-744-5p, and its downstream target gene was SOX12. miR-544-5p expression was decreased, while SOX12 expression was increased in OC tumor tissues and cells. Overexpression of miR-744-5p inhibited cell proliferation, migration, invasion and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. Conclusion MNX1-AS1 promoted the development of OC through miR-744-5p/SOX12 axis. This study revealed a novel mechanism of MNX1-AS1 in OC, which may provide a new treatment or scanning target for OC.

scholarly journals Discoidin Domain Receptor 1 Promotes Hepatocellular Carcinoma Progression through Modulation of SLC1A5 Expression

2021 ◽  
Author(s):  
Yonglong Pan ◽  
Mengzhen Han ◽  
Xiaochao Zhang ◽  
Yi He ◽  
Chaoyi Yuan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Liver Cancer ◽  
Control Cell ◽  
Protein Domain ◽  
Clinical Samples ◽  
Mtorc1 Signaling

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common cancers with the highest mortality rate in the world. Receptor tyrosine kinases play an important role in the occurrence and development of cancer. Discoid protein domain receptors 1 (DDR1) are a special type of transmembrane receptor tyrosine kinase. Here, we show DDR1 is significantly increased in Hepatocellular carcinoma(HCC), which is related to poor prognosis of HCC patients. Methods DDR1 expression in HCC cell lines and paired HCC specimens were determined by western blot and immunohistochemistry (IHC). At the same time, the correlation between the DDR1 and SLC1A5 was also studied in HCC specimens. Cell proliferation ability were evaluated by CCK8 and colony formation assays. Knock-down and overexpression experiments, CHX, NH4CL and Mg132 intervention experiments, Immunoprecipitation experiments, and nude mouse xenograft models were used to determine the potential mechanism by which DDR1 promotes tumorigenesis in vitro and in vivo. Results In this study, we find that overexpression of DDR1 promotes the proliferation of HCC cells and accelerates the growth of tumor xenografts, while downregulation of DDR1 has the opposite effect. We also proved that loss or gain of DDR1 could affect the cell cycle progression of liver cancer cells. Mechanistically, DDR1 interacts with the SLC1A5 that belongs to the solute carrier (SLC) family of transporters and regulates its stability, thereby regulating the mTORC1 signaling pathway. In addition, we found that the regulation of SLC1A5 by DDR1 can be restored by lysosome inhibitors. Otherwise, we found that DDR1 was highly expressed in HCC and elevated DDR1 expression predicted shorter overall survival (OS) time for HCC patients. We further revealed that the expression of SLC1A5 was positively correlated with DDR1.In summary, our data shows that DDR1 is a tumor-promoting factor that can control cell proliferation and cell cycle by stabilizing SLC1A5 in a lysosome-dependent pathway, which provides a new treatment target for HCC. Conclusions This study reveals a new mechanism through which DDR1 can play the role of cancer-promoting genes in the progression of liver cancer. We also found that the expression of DDR1 is an independent prognostic indicator of OS, and the expression of DDR1 and SLC1A5 are positively correlated in clinical samples. Our findings provide a new perspective for understanding the development of HCC, which may provide new targets for the treatment and management of this challenging cancer.

The Role of Retinoblastoma Protein in Cell Cycle Regulation: An Updated Review

2021 ◽  
Vol 20 ◽  
Author(s):  
Rabih Roufayel ◽  
Rabih Mezher ◽  
Kenneth B. Storey
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Cell Cycle Control ◽  
Expression Of Genes ◽  
E2f Transcription Factor ◽  
Cellular Energetics ◽  
Development And Differentiation ◽  
E2f Transcription Factors ◽  
Rb Phosphorylation

: Selected transcription factors have critical roles to play in organism survival by regulating the expression of genes that control the adaptations needed to handle stress conditions. The retinoblastoma (Rb) protein coupled with the E2F transcription factor family was demonstrated to have roles in controlling the cell cycle during freezing and associated environmental stresses (anoxia, dehydration). Rb phosphorylation or acetylation at different sites provide a mechanism for repressing cell proliferation that is under the control of E2F transcription factors in animals facing stresses that disrupt cellular energetics or cell volume controls. Other central regulators of the cell cycle including Cyclins, Cyclin dependent kinases (Cdks), and checkpoint proteins detect DNA damage or any improper replication, blocking further progression of cell cycle and interrupting cell proliferation. This review provides an insight into the molecular regulatory mechanisms of cell cycle control, focusing on Rb-E2F along with Cyclin-Cdk complexes typically involved in development and differentiation that need to be regulated in order to survive extreme cellular stress.

Inhibition of Proliferation and Induction of Apoptosis by Thymoquinone via Modulation of TGF Family, p53, p21 and Bcl-2α in Leukemic Cells

2018 ◽  
Vol 18 (2) ◽  
pp. 210-215 ◽  
Author(s):  
Mona Diab-Assaf ◽  
Josiane Semaan ◽  
Marwan El-Sabban ◽  
Soad K. Al Jaouni ◽  
Rania Azar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cell ◽  
Flow Cytometric Analysis ◽  
Leukemic Cells ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Apoptosis Induction ◽  
Inhibition Of Proliferation ◽  
Human T Cell

Introduction: Adult T-cell leukemia (ATL) is an aggressive form of malignancy caused by human T- cell lymphotropic virus 1 (HTLV-1). Currently, there is no effective treatment for ATL. Thymoquinone has been reported to have anti-cancer properties. Objective: The aim of this study is to investigatthe effects of TQ on proliferation, apoptosis induction and the underlying mechanism of action in both HTLV-1 positive (C91-PL and HuT-102) and HTLV-1 negative (CEM and Jurkat) malignant T-lymphocytes. Materials and Methods: Cells were incubated with different thymoquinone concentrations for 24h. Cell cytotoxicity was assayed using the CytoTox 96® Non-Radioactive Cytotoxicity Assay Kit. Cell proliferation was determined using CellTiter 96® Non-Radioactive Cell Proliferation. Cell cycle analysis was performed by staining with propidium iodide. Apoptosis was assessed using cell death ELISA kit. The effect of TQ on p53, p21, Bcl-2 protein expression was determined using Western blot analysis while TGF mRNA expression was determined by RT-PCR. Results: At non-cytotoxic concentrations of TQ, it resulted in the inhibition of proliferation in a dose dependent manner. Flow cytometric analysis revealed a shift in the cell cycle distribution to the PreG1 phase which is a marker of apoptosis. Also TQ increase DNA fragmentation. TQ mediated its anti-proliferative effect and apoptosis induction by an up-regulation of TGFβ1, p53 and p21 and a down-regulation of TGF-α and Bcl-2α. Conclusion: Thymoquinone presents antiproliferative and proapoptotic effects in ATL cells. For this reason, further research is required to investigate its possible application in the treatment of ATL.

scholarly journals Follicle-Stimulating Hormone Inhibits Adenosine 5′-Monophosphate-Activated Protein Kinase Activation and Promotes Cell Proliferation of Primary Granulosa Cells in Culture through an Akt-Dependent Pathway

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 929-935 ◽  
Author(s):  
Pradeep P. Kayampilly ◽  
K. M. J. Menon
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Protein Kinase ◽  
Mrna Expression ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Ampk Activation ◽  
Cyclin D2 ◽  
Cell Cycle Inhibitor ◽  
Dependent Pathway

FSH, acting through multiple signaling pathways, regulates the proliferation and growth of granulosa cells, which are critical for ovulation. The present study investigated whether AMP-activated protein kinase (AMPK), which controls the energy balance of the cell, plays a role in FSH-mediated increase in granulosa cell proliferation. Cells isolated from immature rat ovaries were grown in serum-free, phenol red free DMEM-F12 and were treated with FSH (50 ng/ml) for 0, 5, and 15 min. Western blot analysis showed a significant reduction in AMPK activation as observed by a reduction of phosphorylation at thr 172 in response to FSH treatment at all time points tested. FSH also reduced AMPK phosphorylation in a dose-dependent manner with maximum inhibition at 100 ng/ml. The chemical activator of AMPK (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, 0.5 mm) increased the cell cycle inhibitor p27 kip expression significantly, whereas the AMPK inhibitor (compound C, 20 μm) and FSH reduced p27kip expression significantly compared with control. FSH treatment resulted in an increase in the phosphorylation of AMPK at ser 485/491 and a reduction in thr 172 phosphorylation. Inhibition of Akt phosphorylation using Akt inhibitor VIII reversed the inhibitory effect of FSH on thr 172 phosphorylation of AMPK, whereas ERK inhibitor U0126 had no effect. These results show that FSH, through an Akt-dependent pathway, phosphorylates AMPK at ser 481/495 and inhibits its activation by reducing thr 172 phosphorylation. AMPK activation by 5-amino-imidazole-4-carboxamide-1-β-d-ribofuranoside treatment resulted in a reduction of cell cycle regulatory protein cyclin D2 mRNA expression, whereas FSH increased the expression by 2-fold. These results suggest that FSH promotes granulosa cell proliferation by increasing cyclin D2 mRNA expression and by reducing p27 kip expression by inhibiting AMPK activation through an Akt-dependent pathway. FSH stimulates granulosa cell proliferation by reducing cell cycle inhibitor p27 kip through AMP kinase inhibition.

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