A feedback regulation of CREB activation through the CUL4A and ERK signaling

Ashok, Cheemala; Owais, Sheikh; Srijyothi, Loudu; Selvam, Murugan; Ponne, Saravanaraman; Baluchamy, Sudhakar

doi:10.1007/s12032-018-1240-2

Cited by 12 publications

(6 citation statements)

References 41 publications

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“…Recent studies have indicated that they exert inhibitory effects on PASMc proliferation (38,39). It has also been reported that the suppression of proliferative signaling, such as ERK1/2 can inhibit the degradation of p27 and p21 (40). The results of the present study demonstrated that ASIV upregulated the protein expression of p27 and p21 in HPASMcs.…”

Section: Discussionsupporting

confidence: 69%

Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling

et al. 2020

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Pulmonary arterial hypertension (PAH) is associated with increased inflammation and abnormal vascular remodeling. Astragaloside IV (ASIV), a purified small molecular saponin contained in the well-know herb, Astragalus membranaceus , is known to exert anti-inflammatory and anti-proliferation effects. Thus, the present study investigated the possible therapeutic effects of ASIV on monocrotaline (MCT)-induced PAH. Rats were administered a single intraperitoneal injection of MCT (60 mg/kg), followed by treatment with ASIV at doses of 10 and 30 mg/kg once daily for 21 days. Subsequently, right ventricle systolic pressure, right ventricular hypertrophy and serum inflammatory cytokines, as well as pathological changes of the pulmonary arteries, were examined. The effects of ASIV on the hypoxia-induced proliferation and apoptotic resistance of human pulmonary artery smooth muscle cells (HPASMCs) and the dysfunction of human pulmonary artery endothelial cells (HPAECs) were evaluated. MCT elevated pulmonary artery pressure and promoted pulmonary artery structural remodeling and right ventricular hypertrophy in the rats, which were all attenuated by both doses of ASIV used. Additionally, ASIV prevented the increase in the TNF-α and IL-1β concentrations in serum, as well as their gene expression in lung tissues induced by MCT. In in vitro experiments, ASIV attenuated the hypoxia-induced proliferation and apoptotic resistance of HPASMCs. In addition, ASIV upregulated the protein expression of p27, p21, Bax, caspase-9 and caspase-3, whereas it downregulated HIF-1α, phospho-ERK and Bcl-2 protein expression in HPASMCs. Furthermore, in HPAECs, ASIV normalized the increased release of inflammatory cytokines and the increased protein levels of HIF-1α and VEGF induced by hypoxia. On the whole, these results indicate that ASIV attenuates MCT-induced PAH by improving inflammation, pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and resistance to apoptosis.

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Section: Discussionsupporting

confidence: 69%

Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling

et al. 2020

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“…Using GSEA software, 20 we conducted GSEA on the primary RNA-seq data pre-Rx and day 28 of cirmtuzumab treatment. We focused GSEA on genes regulated by transcription factors activated by phosphorylated ERK1/2, 21 namely genes targeted by E-twenty-six (Ets-1), 21 , 22 E-26-oncogene (Elk), 21 Hypoxia-inducible factor-1 (HIF-1), 23 Jun, 24 CREB, 25 or Fos. 21 Each gene set was considered significant when the false discovery rate (FDR) was less than 25%.…”

Section: Methodsmentioning

confidence: 99%

Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism

et al. 2020

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Patients with chronic lymphocytic leukemia (CLL) have high plasma-levels of Wnt5a, which can induce phosphorylation of ERK1/2 and enhance CLL-cell proliferation. Such effects could be inhibited by treatment with an ERK1/2 inhibitor, ERK1/2-specific siRNA, or cirmtuzumab, an anti-ROR1 mAb. The CLL-derived line, MEC1, expresses Wnt5a, but not ROR1. MEC1 cells transfected to express ROR1 (MEC1-ROR1) had higher levels of phosphorylated ERK1/2 than parental MEC1, or MEC1 transfected with ROR1ΔPRD, a truncated ROR1 lacking the cytoplasmic proline-rich domain (PRD), or ROR1P808A a mutant ROR1 with a P→A substitution at 808, which is required for complexing with the Rac-specific-guanine-nucleotide-exchange factor DOCK2 upon stimulation with Wnt5a. We silenced DOCK2 with siRNA and found this repressed the capacity of Wnt5a to induce ERK1/2 phosphorylation in MEC1-ROR1 or CLL cells. CLL cells that expressed ROR1 had higher levels of phosphorylated ERK1/2 or DOCK2 than CLL cells lacking ROR1. Although we found ibrutinib could inhibit the phosphorylation of ERK1/2 and DOCK2 induced by B-cell-receptor ligation, we found that this drug was unable to inhibit Wnt5a-induced, ROR1-dependent phosphorylation of ERK1/2 or DOCK2. This study demonstrates that Wnt5a can induce activation of ERK1/2 and enhance CLL-cell proliferation via a ROR1/DOCK2-dependent pathway independent of BTK.

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“…For example, a study on the Wnt-dependent regulation of p27 KIP1 unexpectedly showed that the TCF/LEF1 complex bound to and activated the promoter of mouse Cul4a ( 39 ). A recent study reported that cyclic adenosine monophosphate response element–binding protein (CREB) bound to the cyclic adenosine monophosphate responsive element located in the −926/−764 of CUL4A and activated its transcription ( 40 ). The present results revealed that the −230 bp fragment of the 5′-flanking sequence of CUL4A did not contain TCF/LEF1 or CREB-binding motifs but was still responsive to the KD of Keap1, indicating that neither the Wnt pathway nor CREB are involved in this context.…”

Section: Discussionmentioning

confidence: 99%

Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2

Siswanto

Oguro

Imaoka

2021

Journal of Biological Chemistry

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Nuclear factor erythroid 2–related factor 2 (Nrf2) is a critical transcription factor that orchestrates cellular responses to oxidative stress. Because the dysregulation of Nrf2 has been implicated in many diseases, precise regulation of its protein level is crucial for maintaining homeostasis. Kelch-like-ECH-associated protein 1 (Keap1) and WD40 repeat protein 23 (WDR23) directly regulate Nrf2 levels via similar but distinct proteasome-dependent pathways. WDR23 forms a part of the WDR23-Cullin 4A-RING ubiquitin ligase complex (CRL4A WDR23 ), whereas Keap1 serves as a substrate adaptor for the Cullin 3–containing ubiquitin ligase complex. However, the mechanisms underlying crosstalk between these Keap1 and WDR23 pathways for the regulation of Nrf2 levels have not been investigated. Here, we showed that knockdown (KD) of Keap1 upregulated the expression of Cullin4A ( CUL4A ) in a specificity protein 1 (Sp1)–dependent manner. We also revealed that Sp1 interacted with Keap1, leading to ubiquitination of Sp1. Increases in Sp1 by Keap1 KD triggered Sp1 binding to the fourth Sp1 binding site (Sp1_M4) within the −230/+50 region of the CUL4A gene. We also demonstrated that the overexpression and KD of Sp1 reduced and increased Nrf2 protein levels, respectively. These effects were abrogated by the WDR23 KD, suggesting that Sp1 also regulates Nrf2 levels via the ubiquitin ligase complex CRL4A WDR23 . In conclusion, we discovered Sp1 as a novel substrate of Keap1 and provided evidence that Sp1 regulates the expression of CUL4A . We revealed a novel role for Sp1 in mediating crosstalk between two independent regulators of Nrf2 protein levels.

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A feedback regulation of CREB activation through the CUL4A and ERK signaling

Cited by 12 publications

References 41 publications

Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling

Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling

Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism

Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2

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