Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells

Altman, Molly K.; Alshamrani, Ali A.; Jia, Wei; Nguyen, Ha Thi Thu; Fambrough, Jada M.; Tran, Sterling; Patel, Mihir; Hoseinzadeh, Pooya; Beedle, Aaron M.; Murph, Mandi M.

doi:10.1016/j.canlet.2015.08.012

Cited by 26 publications

(17 citation statements)

References 30 publications

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“…Recent publications have linked a number of RGS proteins to various cancers, including RGS5 in squamous cell carcinoma and ovarian cancer (67,68), RGS6 in urinary bladder cancer (69) and breast cancer (70), and RGS17 in hepatocellular carcinoma, prostate cancer, and some lung cancers (71). More specifically, in ovarian cancer, decreased expression of RGS10 and RGS2 results in cell proliferation and increased chemoresistance (72,73). To contrast this report, it was found that increased expression of RGS19 promoted proliferation (74).…”

Section: Rgs In Cancermentioning

confidence: 67%

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

O’Brien

Wilkinson

Roman

2019

Journal of Biological Chemistry

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Edited by Henrik G. Dohlman G protein-coupled receptors (GPCRs) play critical roles in regulating processes such as cellular homeostasis, responses to stimuli, and cell signaling. Accordingly, GPCRs have long served as extraordinarily successful drug targets. It is therefore not surprising that the discovery in the mid-1990s of a family of proteins that regulate processes downstream of GPCRs generated great excitement in the field. This finding enhanced the understanding of these critical signaling pathways and provided potentially new targets for pharmacological intervention. These regulators of G-protein signaling (RGS) proteins were viewed by many as nodes downstream of GPCRs that could be targeted with small molecules to tune signaling processes. In this review, we provide a brief overview of the discovery of RGS proteins and of the gradual and continuing discovery of their roles in disease states, focusing particularly on cancer and neurological disorders. We also discuss high-throughput screening efforts that have led to the discovery first of peptide-based and then of small-molecule inhibitors targeting a subset of the RGS proteins. We explore the unique mechanisms of RGS inhibition these chemical tools have revealed and highlight the most up-to-date studies using these tools in animal experiments. Finally, we discuss the future opportunities in the field, as there are clearly more avenues left to be explored and potentials to be realized.

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Section: Rgs In Cancermentioning

confidence: 67%

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

O’Brien

Wilkinson

Roman

2019

Journal of Biological Chemistry

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“…More specifically, RGS10 suppresses NF-kB activation and the expression of inflammatory genes such as TNF-a, interleukins, COX-2 and iNOS in multiple types of (resident and recruited) macrophages (18-20, 23, 24). Several studies have investigated the role of RGS10 in inflammation-associated diseases, such Parkinson's disease (23), multiple sclerosis (33), thioglycolate-induced peritonitis (19), osteopetrosis (34)(35)(36), cardiac hypertrophy (37), chemoresistant ovarian cancer (38)(39)(40)(41), platelets aggregation and thrombogenesis (42)(43)(44)(45)(46), obesity and related metabolic syndromes (47), rheumatoid arthritis (48), and colitis-related neurologic dysfunction (49).…”

Section: Discussionmentioning

confidence: 99%

RGS10 Reduces Lethal Influenza Infection and Associated Lung Inflammation in Mice

et al. 2021

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Seasonal influenza epidemics represent a significant global health threat. The exacerbated immune response triggered by respiratory influenza virus infection causes severe pulmonary damage and contributes to substantial morbidity and mortality. Regulator of G-protein signaling 10 (RGS10) belongs to the RGS protein family that act as GTPase activating proteins for heterotrimeric G proteins to terminate signaling pathways downstream of G protein-coupled receptors. While RGS10 is highly expressed in immune cells, in particular monocytes and macrophages, where it has strong anti-inflammatory effects, its physiological role in the respiratory immune system has not been explored yet. Here, we show that Rgs10 negatively modulates lung immune and inflammatory responses associated with severe influenza H1N1 virus respiratory infection in a mouse model. In response to influenza A virus challenge, mice lacking RGS10 experience enhanced weight loss and lung viral titers, higher mortality and significantly faster disease onset. Deficiency of Rgs10 upregulates the levels of several proinflammatory cytokines and chemokines and increases myeloid leukocyte accumulation in the infected lung, markedly neutrophils, monocytes, and inflammatory monocytes, which is associated with more pronounced lung damage. Consistent with this, influenza-infected Rgs10-deficent lungs contain more neutrophil extracellular traps and exhibit higher neutrophil elastase activities than wild-type lungs. Overall, these findings propose a novel, in vivo role for RGS10 in the respiratory immune system controlling myeloid leukocyte infiltration, viral clearance and associated clinical symptoms following lethal influenza challenge. RGS10 also holds promise as a new, potential therapeutic target for respiratory infections.

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“…These results show that miR-199b-5p might play an important role in the activation of the AKT/mTOR signaling pathway. A previous study reported that RGS10 silencing results in mTOR pathway activation in ovarian cancer cells ( 35 ) and that RGS10 overexpression inhibits AKT phosphorylation and regulates cell apoptosis in ovarian cancer cells ( 36 ). These findings indicate that RGS10 could exert biological functions by activating the AKT/mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

miR‑199b‑5p mediates adriamycin‑induced podocyte apoptosis by inhibiting the expression of RGS10

Dai

et al. 2021

Exp Ther Med

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Podocyte apoptosis is a key risk factor for the progression of kidney diseases. MicroRNA (miR)-199b-5p has been shown to be involved in cell apoptosis. However, the molecular mechanisms of miR-199b-5p in podocyte apoptosis remain uncertain. Thus, the present study aimed to investigate whether miR-199b-5p participates in the regulation of podocyte apoptosis and to elucidate the involved mechanisms of this process. A podocyte apoptosis model was constructed using adriamycin (ADR) in vitro . miR-199b-5p mimic and inhibitor were transfected in podocytes to change the expression level of miR-199b-5p. RNA expression was examined by reverse transcription-quantitative PCR. Western blotting was used to measure protein expression. Apoptosis was monitored via flow cytometry and detection of apoptosis-associated proteins. The results from the present study demonstrated that miR-199b-5p was upregulated and that regulator of G-protein signaling 10 (RGS10) was downregulated in ADR-stimulated podocytes. Overexpression of miR-199b-5p could inhibit RGS10 expression and stimulate podocyte apoptosis, whereas miR-199b-5p knockdown restored the levels of RGS10 and ameliorated podocyte apoptosis in ADR-induced podocytes. Furthermore, the effects of miR-199b-5p overexpression could be significantly reversed by RGS10 overexpression. In addition, podocyte transfection of miR-199b-5p activated the AKT/mechanistic target of rapamycin (mTOR) signaling, which was blocked following RGS10 overexpression. Taken together, the present study demonstrated that miR-199b-5p upregulation could promote podocyte apoptosis by inhibiting the expression of RGS10 through the activation of AKT/mTOR signaling.

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Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells

Cited by 26 publications

References 30 publications

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

RGS10 Reduces Lethal Influenza Infection and Associated Lung Inflammation in Mice

miR‑199b‑5p mediates adriamycin‑induced podocyte apoptosis by inhibiting the expression of RGS10

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