Mutations leading to constitutive active gp130/JAK1/STAT3 pathway

Pilati, Camilla; Zucman‐Rossi, Jessica

doi:10.1016/j.cytogfr.2015.07.010

Cited by 51 publications

(41 citation statements)

References 99 publications

(131 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3A). In human GSD-Ia patients with HCA/HCC nodules, there are multiple nodules per liver [9, 10]. In untreated L- G6pc−/− mice [19] a similar pattern is seen.…”

Section: Resultsmentioning

confidence: 91%

“…In contrast, the inflammatory HCA is characterized by a constitutive activation of the signal transducer and activator of transcription 3 (STAT3), a cancer-promoting transcription factor [10]. In the current study, we showed that the levels of mRNA for Glul and Lgr5 were increased in HCC-1, suggesting that HCC-1 was derived from a β-catenin mutated HCA and the levels of the active p-STAT3-Y705 protein were increased in HCC-2, suggesting that HCC-2 was derived from an inflammatory HCA.…”

Section: Resultsmentioning

confidence: 99%

“…In 10% cases, HCA undergoes malignant transformation to hepatocellular carcinoma (HCC). In GSD patients classified to date, 52% of HCA are inflammatory HCA, 28% β-catenin mutated HCA and 20% unclassified HCA [9, 10]. …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors

Kim

Lee

Kwon

et al. 2017

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC). We have previously shown that G6pc−/− mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase-α, and expressing 3–63% of normal hepatic G6Pase-α activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-α activity required to prevent tumor formation remained unknown. In this study, we constructed rAAV-co-G6PC, a rAAV vector expressing a codon-optimized (co) G6Pase-α and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-α expression. Over an 88-week study, we showed that both rAAV-G6PC- and rAAV-co-G6PC-treated G6pc−/− mice expressing 3–33% of normal hepatic G6Pase-α activity (AAV mice) maintained glucose homeostasis, lacked HCA/HCC, and were protected against age-related obesity and insulin resistance. Of the eleven rAAV-G6PC/rAAV-co-G6PC-treated G6pc−/− mice harboring 0.9–2.4% of normal hepatic G6Pase-α activity (AAV-low mice), 3 expressing 0.9–1.3% of normal hepatic G6Pase-α activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the AAV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing ≥ 3% of normal hepatic G6Pase-α activity. The results establish the threshold of hepatic G6Pase-α activity required to prevent HCA/HCC and show that GSD-Ia mice harboring less than 2% of normal hepatic G6Pase-α activity are at risk of tumor development.

show abstract

“…3A). In human GSD-Ia patients with HCA/HCC nodules, there are multiple nodules per liver [9, 10]. In untreated L- G6pc−/− mice [19] a similar pattern is seen.…”

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors

Kim

Lee

Kwon

et al. 2017

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

show abstract

“…Although most intensively studied for their important roles in cytokine signaling, modulating the immune response and oncogenesis, mutations in the proteins present in this pathway, including Jak1, cause a number of different diseases, 33,34 and are responsible for numerous hepatocellular adenomas. 35 Additionally, the pathway is evolutionarily conserved and functions in transducing extracellular stimuli to the transcriptional apparatus. 36 However, while Jak1 is expressed in both heart and muscle (GeneCard database), Jak1’s role in normal and diseased cardiomyocytes is relatively unexplored.…”

Section: Resultsmentioning

confidence: 99%

An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels

McLendon

Davis

Gulick

et al. 2017

Circulation Research

View full text Add to dashboard Cite

Rationale Post-mitotic cells such as cardiomyocytes appear to be particularly susceptible to proteotoxic stimuli, and large, proteinaceous deposits are characteristic of the Desmin Related Cardiomyopathies and crystallin cardiomyopathic diseases. Increased activity of protein clearance pathways in the cardiomyocyte such as proteasomal degradation and autophagy have proven to be beneficial in maintaining cellular and cardiac function in the face of multiple proteotoxic insults, holding open the possibility of targeting these processes for the development of effective therapeutics. Objective Here we undertake an unbiased, total genome screen for RNA transcripts and their protein products that impact on aggregate accumulations in the cardiomyocytes. Methods and Results Primary mouse cardiomyocytes that accumulate aggregates as a result of a mutant αB crystallin causative for human Desmin Related Cardiomyopathy were used for a total genome-wide screen to identify gene products that impacted on aggregate formation. We infected cardiomyocytes using a short hairpin RNA lentivirus library in which the mouse genome was represented. The screen identified multiple candidates in a number of cell signaling pathways that were able to mediate significant decreases in aggregate levels. Conclusions Subsequent validation of one of these candidates, Janus kinase 1 (Jak1), a tyrosine kinase of the non-receptor type, confirmed the usefulness of this approach in identifying previously unsuspected players in proteotoxic processes.

show abstract

“…STAT3 contributes to cancer development and progression [154–156] and is activated in many cancer types including glioblastoma, breast, prostate, liver, and pancreas [157–160]. STAT3 signaling contributes to tumor cell proliferation, survival, angiogenesis, metastatic potential, immunosuppression, and chemoresistance [17,161].…”

Section: 0 Stat3 Outside Muscle In Cachexiamentioning

confidence: 99%

STAT3 in the systemic inflammation of cancer cachexia

Zimmers

Fishel

Bonetto

2016

Seminars in Cell & Developmental Biology

194

166

View full text Add to dashboard Cite

Weight loss is diagnostic of cachexia, a debilitating syndrome contributing mightily to morbidity and mortality in cancer. Most research has probed mechanisms leading to muscle atrophy and adipose wasting in cachexia; however cachexia is a truly systemic phenomenon. Presence of the tumor elicits an inflammatory response and profound metabolic derangements involving not only muscle and fat, but also the hypothalamus, liver, heart, blood, spleen and likely other organs. This global response is orchestrated in part through circulating cytokines that rise in conditions of cachexia. Exogenous Interleukin-6 (IL6) and related cytokines can induce most cachexia symptomatology, including muscle and fat wasting, the acute phase response and anemia, while IL-6 inhibition reduces muscle loss in cancer. Although mechanistic studies are ongoing, certain of these cachexia phenotypes have been causally linked to the cytokine-activated transcription factor, STAT3, including skeletal muscle wasting, cardiac dysfunction and hypothalamic inflammation. Correlative studies implicate STAT3 in fat wasting and the acute phase response in cancer cachexia. Parallel data in non-cancer models and disease states suggest both contributory and protective functions for STAT3 in other organs during cachexia. Finally, STAT3 contributes to cancer cachexia through enhancing tumorigenesis, metastasis and immune suppression, particularly in tumors associated with high prevalence of cachexia. This review examines the evidence linking STAT3 to multi-organ manifestations of cachexia in cancer and evidence for targeting STAT3 for anti-cachexia therapies.

show abstract

Mutations leading to constitutive active gp130/JAK1/STAT3 pathway

Cited by 51 publications

References 99 publications

Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors

Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors

An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels

STAT3 in the systemic inflammation of cancer cachexia

Contact Info

Product

Resources

About