JAK/STAT Signaling Is Associated With Cardiac Dysfunction During Ischemia and Reperfusion

Mascareno, Eduardo; El-Shafei, M. E.; Maulik, Nilanjana; Sato, Motoaki; Guo, Yanjuan; Das, Dipak K.; Siddiqui, M.A.Q.

doi:10.1161/01.cir.104.3.325

Cited by 168 publications

(130 citation statements)

References 29 publications

(31 reference statements)

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“…We conclude that CIITA PIV promoter can be activated in injured kidneys by an IFN-independent pathway, a response of particular interest in relationship to autoimmunity and allograft rejection. A strong candidate for IFN-independent PIV activation could be the JAK/STAT pathway that is a significant factor in myocardial ischemia (39) and ischemic brain injury (40). Injury-related PI activation, on the other hand, could reflect accumulation of the class II-positive interstitial cells that occurs several days after renal injury.…”

Section: Discussionmentioning

confidence: 99%

Differential Usage of Class II Transactivator Promoters PI and PIV during Inflammation and Injury in Kidney

Takeuchi

Sims²,

Takei³

et al. 2003

Journal of the American Society of Nephrology

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Section: Discussionmentioning

confidence: 99%

Differential Usage of Class II Transactivator Promoters PI and PIV during Inflammation and Injury in Kidney

Takeuchi

Sims²,

Takei³

et al. 2003

Journal of the American Society of Nephrology

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“…Expression of AGT, a precursor of the signaling molecule AgtII, is regulated in a tissue-specific manner (34)(35)(36)(37). In heart tissue, AgtII activates Jak1, Jak2, and Tyk2, resulting in activation of STATs (38).…”

Section: Invasiveness and Tumor Cell Dissemination Requires Regulatiomentioning

confidence: 99%

Genetic reprogramming of tumor cells by zinc finger transcription factors

Blancafort

Chen

González

et al. 2005

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

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Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cell phenotypes remains a formidable obstacle. Herein, we describe an alternative genetic approach for identification of genes involved in tumor progression by using a library of zinc finger artificial transcription factors (ATFs) and functional screening of tumor cells as a source of genetic plasticity and clonal selection. We isolated a six-zinc finger transcriptional activator (TF 20-VP, TF 20 containing the VP64 activator domain) that acts to reprogram a drug-sensitive, poorly invasive, and nonmetastatic cell line into a cell line with a drugresistant, highly invasive, and metastatic phenotype. Differential expression profiles of cells expressing TF 20-VP followed by functional studies, both in vitro and in animal models, revealed that invasion and metastasis requires coregulation of multiple target genes. Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP. We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo. This study demonstrates the use of ATFs to identify the group of genes that cooperate during tumor progression. By coregulating multiple targets, ATFs can be used as master genetic switches to reprogram and modulate complex neoplastic phenotypes. drug resistance ͉ metastasis ͉ invasion ͉ transcriptional regulation ͉ RNA inteference

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“…Studies in fetal murine cardiac myocytes infected with adenovirus carrying wild-type or mutated STAT3 cDNA suggested that the STAT3-dependent signaling pathway plays a role in promoting the hypertrophy induced by leukemia inhibitory factor (LIF), a member of IL-6-related cytokines (26). In addition, activation of the JAK/STAT signaling pathway in rat heart has been associated with the cardiac hypertrophy stimulated by cardiotrophin-1, another member of IL-6-related cytokines (27), and with cardiac dysfunction during ischemia and reperfusion (28), myocardial ischemia (29), and acute myocardial infarction (30). Although different isoforms of JAK/STAT have been associated with effects of IL-6-related cytokines in adult rat heart, direct links between IL-6 stimulation, activation of JAK/ STAT, and IL-6-induced cardiac inotropic actions have not been established.…”

Section: Il-6mentioning

confidence: 99%

JAK2/STAT3, Not ERK1/2, Mediates Interleukin-6-induced Activation of Inducible Nitric-oxide Synthase and Decrease in Contractility of Adult Ventricular Myocytes

Kennedy

Liu

2003

Journal of Biological Chemistry

134

119

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Interleukin (IL)-6 decreases cardiac contractility via a nitric oxide (NO)-dependent pathway. However, mechanisms underlying IL-6-induced NO production remain unclear. JAK2/STAT3 and ERK1/2 are two well known signaling pathways activated by IL-6 in non-cardiac cells. However, these IL-6-activated pathways have not been identified in adult cardiac myocytes. In this study, we identified activation of these two pathways during IL-6 stimulation and examined their roles in IL-6-induced NO production and decrease in contractility of adult ventricular myocytes. IL-6 increased phosphorylation of STAT3 (at Tyr 705 ) and ERK1/2 (at Tyr 204 ) within 5 min that peaked at 15-30 min and returned to basal levels at 2 h. Phosphorylation of STAT3 was blocked by genistein, a protein tyrosine kinase inhibitor, and AG490, a JAK2 inhibitor, but not PD98059, an ERK1/2 kinase inhibitor. The phosphorylation of ERK1/2 was blocked by PD98059 and genistein but not AG490. Furthermore, IL-6 enhanced de novo synthesis of iNOS protein, increased NO production, and decreased cardiac contractility after 2 h of incubation. These effects were blocked by genistein and AG490 but not PD98059. We conclude that IL-6 activated independently the JAK2/STAT3 and ERK1/2 pathways, but only JAK2/ STAT3 signaling mediated the NO-associated decrease in contractility.

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JAK/STAT Signaling Is Associated With Cardiac Dysfunction During Ischemia and Reperfusion

Cited by 168 publications

References 29 publications

Differential Usage of Class II Transactivator Promoters PI and PIV during Inflammation and Injury in Kidney

Differential Usage of Class II Transactivator Promoters PI and PIV during Inflammation and Injury in Kidney

Genetic reprogramming of tumor cells by zinc finger transcription factors

JAK2/STAT3, Not ERK1/2, Mediates Interleukin-6-induced Activation of Inducible Nitric-oxide Synthase and Decrease in Contractility of Adult Ventricular Myocytes

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