Jak2 Tyrosine Kinase Mediates Oxidative Stress-induced Apoptosis in Vascular Smooth Muscle Cells

Sandberg, Eric M.; Sayeski, Peter P.

doi:10.1074/jbc.m405045200

Cited by 61 publications

(37 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Treatment with the JAK2 inhibitor AG490 (ref. 39) or the STAT5 inhibitor nicotinoyl hydrazone 40 led to upregulation of MSI1 in the oncospheres ( Fig. 5b,c ).…”

Section: Resultsmentioning

confidence: 89%

Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs

Oskarsson

Acharyya

Zhang

et al. 2011

Nat Med

761

703

View full text Add to dashboard Cite

We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell–derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat–containing G protein– coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell– derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.

show abstract

“…Treatment with the JAK2 inhibitor AG490 (ref. 39) or the STAT5 inhibitor nicotinoyl hydrazone 40 led to upregulation of MSI1 in the oncospheres ( Fig. 5b,c ).…”

Section: Resultsmentioning

confidence: 89%

Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs

Oskarsson

Acharyya

Zhang

et al. 2011

Nat Med

761

703

View full text Add to dashboard Cite

show abstract

“…Interestingly, several studies have reported cross talk between the insulin receptor kinase and the Janus-activated kinase (JAK) signaling pathways [56-58]. In particular, JAK2 - the major mediator of inflammatory cytokine signaling in mammalian cells - can be activated by hydrogen peroxide [59] and contributes to insulin-dependent activation of p38 MAPK, JNK, and ERK in a manner that is independent of insulin receptor substrate activation and activation of the phosphatidylinositol 3-kinase/Akt-dependent arm of insulin signaling [60]. Jaramillo-Gutierrez et al .…”

Section: Discussionmentioning

confidence: 99%

The mitogen-activated protein kinome from Anopheles gambiae: identification, phylogeny and functional characterization of the ERK, JNK and p38 MAP kinases

et al. 2011

View full text Add to dashboard Cite

BackgroundAnopheles gambiae is the primary mosquito vector of human malaria parasites in sub-Saharan Africa. To date, three innate immune signaling pathways, including the nuclear factor (NF)-kappaB-dependent Toll and immune deficient (IMD) pathways and the Janus kinase/signal transducers and activators of transcription (Jak-STAT) pathway, have been extensively characterized in An. gambiae. However, in addition to NF-kappaB-dependent signaling, three mitogen-activated protein kinase (MAPK) pathways regulated by JNK, ERK and p38 MAPK are critical mediators of innate immunity in other invertebrates and in mammals. Our understanding of the roles of the MAPK signaling cascades in anopheline innate immunity is limited, so identification of the encoded complement of these proteins, their upstream activators, and phosphorylation profiles in response to relevant immune signals was warranted.ResultsIn this study, we present the orthologs and phylogeny of 17 An. gambiae MAPKs, two of which were previously unknown and two others that were incompletely annotated. We also provide detailed temporal activation profiles for ERK, JNK, and p38 MAPK in An. gambiae cells in vitro to immune signals that are relevant to malaria parasite infection (human insulin, human transforming growth factor-beta1, hydrogen peroxide) and to bacterial lipopolysaccharide. These activation profiles and possible upstream regulatory pathways are interpreted in light of known MAPK signaling cascades.ConclusionsThe establishment of a MAPK "road map" based on the most advanced mosquito genome annotation can accelerate our understanding of host-pathogen interactions and broader physiology of An. gambiae and other mosquito species. Further, future efforts to develop predictive models of anopheline cell signaling responses, based on iterative construction and refinement of data-based and literature-based knowledge of the MAP kinase cascades and other networked pathways will facilitate identification of the "master signaling regulators" in biomedically important mosquito species.

show abstract

“…Oxidative stress is increasingly implicated in the development of atherosclerosis (5) and increased oxidative damage, and elevated levels of DNA strand breaks occur in human atherosclerotic plaques (6). Oxidative stress reduces IGF1R expression and induces VSMC apoptosis in culture (7)(8)(9)(10). Reduced IGF1R expression is also seen within plaques, suggesting that IGF1R-dependent survival regulates apoptosis in vivo (11,12).…”

mentioning

confidence: 99%

Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3

Allard

Figg

Bennett

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Apoptosis of vascular smooth muscle cells (VSMCs) may lead to atherosclerotic plaque instability and rupture, resulting in myocardial infarction, stroke, and sudden death. However, the molecular mechanisms mediating survival of VSMCs in atherosclerotic plaques remain unknown. Although plaque VSMCs exhibit increased susceptibility to apoptosis and reduced expression of the IGF1 receptor (IGF1R) when compared with normal VSMCs, a causative effect has not been established. Here we show that increased expression of the IGF1R can rescue plaque VSMCs from oxidative stress-induced apoptosis, demonstrating that IGF-1 signaling is a critical regulator of VSMC survival. Akt mediates the majority of the IGF1R survival signaling, and ectopic activation of Akt was sufficient to protect VSMCs in vitro. Both IGF1R and phospho-Akt expression were reduced in human plaque (intimal) VSMCs when compared with medial VSMCs, suggesting that Akt mediates survival signaling in atherosclerosis. Importantly, downstream targets of Akt were identified that mediate its protective effect as inhibition of FoxO3a or GSK3 by Akt-dependent phosphorylation protected VSMCs in vitro. We conclude that Akt and its downstream targets FoxO3a and GSK3 regulate a survival pathway in VSMCs and that their deregulation due to a reduction of IGF1R signaling may promote apoptosis in atherosclerosis.Insulin-like growth factor 1 (IGF1) 2 is a ubiquitous factor exhibiting pleiotropic effects on different cell types. Stimulation of the IGF1 receptor (IGF1R) initiates signaling pathways involved in cell proliferation, differentiation, transformation, and survival. IGF1R-dependent signaling is crucial for the survival of many cell types including vascular smooth muscle cells (VSMCs). VSMCs are the principle source of collagen and extracellular matrix that maintain the tensile strength of atherosclerotic plaques, and VSMC loss induces multiple features of plaque instability (1). In humans, rupture or erosion of the atherosclerotic plaque underlie the majority of myocardial infarctions, stroke, and sudden death (2). We have previously shown that VSMCs derived from atherosclerotic plaques (pVSMCs) are more sensitive to apoptosis than cells derived from non-diseased vessels (3) and exhibit a defect in IGF1-dependent survival signaling (4). Oxidative stress is increasingly implicated in the development of atherosclerosis (5) and increased oxidative damage, and elevated levels of DNA strand breaks occur in human atherosclerotic plaques (6). Oxidative stress reduces IGF1R expression and induces VSMC apoptosis in culture (7-10). Reduced IGF1R expression is also seen within plaques, suggesting that IGF1R-dependent survival regulates apoptosis in vivo (11,12). However, plaque VSMCs also show increased sensitivity to multiple proapoptotic stimuli, including the tumor suppressor gene P53 and death receptor ligation (13,14). It is therefore not known whether defective IGF1R expression alone is an important cause of reduced survival of pVSMCs.A major downstream effector of IGF1R ...

show abstract

Jak2 Tyrosine Kinase Mediates Oxidative Stress-induced Apoptosis in Vascular Smooth Muscle Cells

Cited by 61 publications

References 24 publications

Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs

Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs

The mitogen-activated protein kinome from Anopheles gambiae: identification, phylogeny and functional characterization of the ERK, JNK and p38 MAP kinases

Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3

Contact Info

Product

Resources

About