Activator protein-1 (AP-1): a bridge between life and death in lung epithelial (A549) cells under hypoxia

Yadav, Seema; Kalra, Namita; Ganju, Lilly; Singh, Mrinalini

doi:10.1007/s11010-017-3082-1

Cited by 30 publications

(25 citation statements)

References 39 publications

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“…p27 is an inhibitor of CDK1 (27). AKT, ERK, AP-1 and NF-κB regulate cyclin B1 expression in cell proliferation (29,30), and AKT and ERK have also been shown to suppress p21 and p27 (31)(32)(33). In this study, following treatment with cerdulatinib, the p21 and p27 protein levels were upregulated relative to those of the control group.…”

Section: Discussionmentioning

confidence: 52%

Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor

2018

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Adult T‑cell leukemia/lymphoma (ATLL) constitutes an aggressive malignancy caused by human T‑cell leukemia virus type 1 (HTLV‑1) that is resistant to available chemotherapeutics. The constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is an important feature of ATLL, and spleen tyrosine kinase (SYK) is overexpressed in HTLV‑1-transformed T‑cell lines. In this study, we evaluated the effects of SYK- (PRT060318) or JAK- (JAK inhibitor 1) selective inhibitors and the dual SYK/JAK inhibitor, cerdulatinib, on the viability of HTLV‑1-transformed and ATLL-derived T‑cell lines. Cell proliferation, viability, cell cycle, apoptosis and intracellular signaling cascades were analyzed by the water-soluble tetrazolium-8 assay, flow cytometry and western blot analysis. HTLV‑1-infected T‑cell lines were sensitive to both SYK-selective and pan-JAK inhibitors, whereas cerdulatinib more potently suppressed cell proliferation and reduced cell viability than either of these agents alone. By contrast, the cytotoxic effects of cerdulatinib on uninfected T‑cell lines and peripheral blood mononuclear cells from a healthy donor were less pronounced. Cerdulatinib induced cell cycle arrest in the G2/M phase, which was associated with a decreased cyclin-dependent kinase 1 and cyclin B1, and an increased p21 and p27 expression. Hoechst staining revealed chromatin condensation and nuclear fragmentation in the cells treated with cerdulatinib, and an increased fraction of apoptotic APO2.7-stained cells was detected by flow cytometry. This corresponded to the activation of caspase-8, -9 and -3, and decreased levels of the anti-apoptotic factors, Bcl-xL, survivin, X-linked inhibitor of apoptosis (XIAP) and c‑FLIP. The cerdulatinib-induced decrease in cell viability was partly reversed by the caspase inhibitor, z‑VAD‑FMK. These anti-ATLL effects were associated with the suppression of SYK and JAK/STAT signaling, along with that of the downstream factors, AKT, ERK, activator protein‑1 and nuclear factor-κB. Finally, oral dosing with cerdulatinib lowered the tumor burden in a murine model of ATLL. Thus, our findings indicate that the simultaneous inhibition of therapeutically relevant targets, such as SYK and JAK is a more effective approach than single-agent therapy for the treatment of ATLL.

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Section: Discussionmentioning

confidence: 52%

Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor

2018

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“…Our previous study also shown that initial hypoxia stress increased the expression of c‐Jun and c‐Fos that led to the formation of stable heterodimer resulting in increased cell proliferation. Whereas, the increased expression of junB under hypoxia caused negative impact over cell proliferation (Yadav et al, ). The DNA binding affinities and transactivation capacities of the Jun proteins vary considerably, with c‐Jun exhibiting the highest activation potential (Ryseck & Bravo, ).…”

Section: Discussionmentioning

confidence: 99%

“…Having confirmed that expression of MAPK family (JNK, ERK, and p38) was altered in hypoxic lung, we evaluated AP-1 transcription factor by EMSA, as MAPK signal transduction pathway uses AP-1 as a converging point to regulate expression of various genes. Nuclear extracts obtained from whole lung exposed to hypobaric hypoxia at (Yadav et al, 2017). The DNA binding affinities and transactivation capacities of the Jun proteins vary considerably, with c-Jun exhibiting the highest activation potential (Ryseck & Bravo, 1991).…”

Section: Discussionmentioning

confidence: 99%

The MAPK‐activator protein‐1 signaling regulates changes in lung tissue of rat exposed to hypobaric hypoxia

Singh

Yadav

Kumar

et al. 2018

Journal Cellular Physiology

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This study reports the role of MAPKs (JNK, ERK, and p38), and activator protein-1 (AP-1) transcription factor in the hypobaric hypoxia induced change in lung tissue. Healthy male Sprague-Dawley rats were exposed to hypobaric hypoxia for 6, 12, 24, 48, 72, and 120 hr. Hypoxia resulted in significant increase in reactive oxygen species (ROS), vascular endothelial growth factor (VEGF) and decreased nitric oxide (NO), these act as signaling molecules for activation of MAPK and also contribute in development of vascular leakage (an indicator of pulmonary edema) as confirmed by histological studies. Our results confirmed JNK activation as an immediate early response (peaked at 6-48 hr), activation of ERKs (peaked at 24-72 hr) and p38 (peaked at 72-120 hr) as a secondary response to hypoxia. The MAPK pathway up regulated its downstream targets phospho c-Jun (peaked at 6-120 hr), JunB (peaked at 24-120 hr) however, decreased c-Fos, and JunD levels. DNA binding activity also confirmed activation of AP-1 transcription factor in lung tissue under hypobaric hypoxia. Further, we analyzed the proliferative and inflammatory genes regulated by different subunits of AP-1 to explore its role in vascular leakage. Increased expression of cyclin D1 (peaked at 12-72 hr) and p16 level (peaked at 48-120 hr) were correlated to the activation of c-jun, c-Fos and JunB. Administration of NFκB inhibitor caffeic acid phenethyl ester (CAPE) and SP600125 (JNK inhibitor) had no effect on increased levels of Interferon-γ (IFN-γ), Interleukin-1 (IL-1), and Tumor Necrosis Factor-α (TNF-α) thereby confirming the involvement of AP-1 as well as NFκB in inflammation. Expression of c-jun, c-Fos were correlated with activation of proliferative genes and JunB, Fra-1 with pro-inflammatory cytokines. In conclusion immediate response to hypobaric hypoxia induced c-Jun:c-Fos subunits of AP-1; responsible for proliferation that might cause inhomogeneous vasoconstriction leading to vascular leakage and inflammation at increased duration of hypobaric hypoxia exposure.

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“…Fos and Jun proteins comprise a heterodimer namely AP-1 (activator protein 1, AP-1), an important transcription factors involved in apoptotic pathway and TNFrelated signaling pathway [49,50] . Thereby AP-1 plays an important role in pathological processes such as proliferation, differentiation, apoptosis, and inflammation of cells [51,52] . The level of Fos expression is affected by several factors.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of MicroRNA-155 Regulated Autophagy and Apoptosis by targeting gene Rictor/Fos in Gastric Cancer Progression

Chen

Ren

et al. 2020

Preprint

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BACKGROUND Microrna-155 plays an important role in the pathogenesis, progression and treatment of various cancers. It is abnormally expressed in gastric cancer, but its expression level, mechanism and significance are controversial in different studies. So we make the study to explore the expression level, significance and mechanism of microRNA-155 on gastric cancer. METHODS Target genes of microRNA-155 in TargetScan and mirDB databases were analyzed by Wayne Mapping, Enrichr database, String database, TIMER database. Forty-three pairs of cancer tissues and adjacent tissues were collected to extract total RNA and protein. Expression of MicroRNA-155, Rictor, Fos, Beclin1, LC3, caspase3 and caspase9 were measured by qRT-PCR and western blot. The relationship between gene expression and clinicopathological factors were analyzed. SPSS 23.0 was used for statistical analysis. RESULTS A total of 700 (miRDB) and 556 (TargetScan) target genes were obtained and 280 genes were in the intersection of Wayne Mapping, 49 of them had a target score of 90 or more. GO and KEGG analysis revealed that they were related to autophagy or apoptosis pathway. Rictor and Fos were selected as research objects. Thirty-two cases showed high microRNA-155 expression (group H) and 11 cases showed low expression (group L). Twelve patients had high Rictor expression and 31 patients had low expression; Thirteen cases had roughly normal Fos expression and 30 cases had low or negative expression; Thirty-three cases had high Beclin1/LC3 expression and 10 cases had low expression; Ten cases had high caspase3/caspase9 expression and 33 cases had low expression. According to the results of immunohistochemistry and western blot, Rictor, Fos, caspase3 and caspase9 were low expressed while Beclin1 and LC3 were high expressed in group H. However, all the six genes had no significant difference in group L. CONCLUSIONS The abnormal expression of microRNA-155 may indicate the occurrence of gastric cancer and its expression level is negatively correlated with clinical stage of cancer. The down-regulated expression of Rictor and Fos, enhancement of autophagy and weakening of apoptosis may be related to the over-expression of microRNA-155. MicroRNA-155 may promote the progression of gastric cancer by promoting autophagy and inhibiting apoptosis.

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Activator protein-1 (AP-1): a bridge between life and death in lung epithelial (A549) cells under hypoxia

Cited by 30 publications

References 39 publications

Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor

Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor

The MAPK‐activator protein‐1 signaling regulates changes in lung tissue of rat exposed to hypobaric hypoxia

Clinical Significance of MicroRNA-155 Regulated Autophagy and Apoptosis by targeting gene Rictor/Fos in Gastric Cancer Progression

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