Toward a new STATe: The role of STATs in mitochondrial function

Meier, Jeremy A.; Larner, Andrew C.

doi:10.1016/j.smim.2013.12.005

Cited by 144 publications

(152 citation statements)

References 78 publications

Supporting

Mentioning

139

Contrasting

Order By: Relevance

“…3A), probably resulting in biased STAT3 activation. A recent study describes the mitochondrial trafficking of caveolin-1 and STAT3 (Meier and Larner 2014). The major portion of STAT3 that associates with nonraft fractions as shown in Figure 3 may account for the mitochondrial localization of STAT3.…”

Section: Discussionmentioning

confidence: 89%

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Ryter

Choi

Kim

2014

Biochem. Cell Biol.

View full text Add to dashboard Cite

Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1(-/-)) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1(-/-) fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1(-/-) liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis.

show abstract

Section: Discussionmentioning

confidence: 89%

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Ryter

Choi

Kim

2014

Biochem. Cell Biol.

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that STAT3 can localize to the mitochondrion, where it promotes oxidative phosphorylation and membrane permeability (Figure 1). This effect is dependent on serine but not tyrosine phosphorylation and is thought to be relevant in settings where cellular respiration is altered, such as cellular stress and cancer (58). All other STATs (save STAT4) have now been detected in the mitochondrion but their function within this organelle has not been rigorously assessed (58).…”

Section: Non-canonical Aspects Of Jak/stat Signalingmentioning

confidence: 99%

“…This effect is dependent on serine but not tyrosine phosphorylation and is thought to be relevant in settings where cellular respiration is altered, such as cellular stress and cancer (58). All other STATs (save STAT4) have now been detected in the mitochondrion but their function within this organelle has not been rigorously assessed (58). Another intriguing ‘geographical’ deviation involves Jak2, which has been shown to mediate p-Tyr of nuclear histones (59).…”

Section: Non-canonical Aspects Of Jak/stat Signalingmentioning

confidence: 99%

Mechanisms of Jak/STAT Signaling in Immunity and Disease

Villarino

Kanno

Ferdinand

et al. 2015

The Journal of Immunology

451

358

View full text Add to dashboard Cite

More than 2 decades ago, experiments on the antiviral mechanisms of interferons led to the discovery of Janus kinases (JAK) and their downstream effectors, the signal transducer of activation (STAT) proteins. This pathway has since become a paradigm for membrane to nucleus signaling and has come to explain how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, but has also become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review will synthesize current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead.

show abstract

“…Phosphorylation at Tyr705 (pTyr705), catalyzed by Janus kinases (JAK) and other tyrosine kinases, induces STAT3 dimerization through the interaction of the SH2 domain (SH2D), nuclear accumulation, and target gene transcription (1,3,4). Emerging evidence indicates that STAT3 also localizes to mitochondria and controls mitochondrial functions (2,(5)(6)(7). Mitochondrial localized STAT3 (mSTAT3) is critical for survival of RAStransformed mouse embryo fibroblasts (MEF) under glucosestarvation, reflecting a specific dependency of cancer cells on mitochondria in certain conditions (6).…”

Section: Opb-51602mentioning

confidence: 99%

Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

Genini

Brambilla

Laurini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3-drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug's ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells. Importantly, the lethal consequences of mSTAT3 inhibition are enhanced by glucose starvation and by increased reliance of cancer cells and tumor-initiating cells on mitochondria, resulting in potent activity in cell cultures and tumor xenografts in mice. These findings can be exploited for eliciting synthetic lethality in metabolically stressed cancer cells using highaffinity STAT3 inhibitors. Thus, this study provides insights on the role of mSTAT3 in cancer cells and a conceptual framework for developing more effective cancer therapies.S ignal transducer and activator of transcription 3 (STAT3) is a key element in multiple signaling pathways and is aberrantly activated in many human cancers (1, 2). STAT3 promotes cell proliferation, survival, angiogenesis, and immune-evasion (1-3). Phosphorylation at Tyr705 (pTyr705), catalyzed by Janus kinases (JAK) and other tyrosine kinases, induces STAT3 dimerization through the interaction of the SH2 domain (SH2D), nuclear accumulation, and target gene transcription (1, 3, 4). Emerging evidence indicates that STAT3 also localizes to mitochondria and controls mitochondrial functions (2, 5-7). Mitochondrial localized STAT3 (mSTAT3) is critical for survival of RAStransformed mouse embryo fibroblasts (MEF) under glucosestarvation, reflecting a specific dependency of cancer cells on mitochondria in certain conditions (6). Interestingly, mSTAT3 is prevalently phosphorylated at Ser727 (pSer727), which enhances its mitochondrial functions (5, 6). Furthermore, constitutive pSer727 is found in many human cancers and is apparently sufficient to drive tumorigenesis in various model systems (8-10).STAT3 is an attractive cancer therapeutic target because of its central role in multiple oncogenic processes and great effort has been devoted in recent years to discover STAT3 inhibitors (STAT3i) (11,12). To date, small-molecule STAT3i have shown relevant activity in preclinical models and few of them are currently investigated in clinical trials (11,(13)(14)(15)(16)(17). However, an important gap persists in our knowledge of the biological mechanisms of antitumor activity, the critical cellular processes affected, and the factors determining sensitivity of cancer cells to STAT3i, hindering further clinical development of these highly promising anticancer drugs. Indeed, great atten...

show abstract

Toward a new STATe: The role of STATs in mitochondrial function

Cited by 144 publications

References 78 publications

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Mechanisms of Jak/STAT Signaling in Immunity and Disease

Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

Contact Info

Product

Resources

About