Alternariol induces DNA polymerase β expression through the PKA-CREB signaling pathway

Zhao, Jimin; Liu, Kangdong; Lü, Junhong; Ma, Jun; Zhang, Xiaoyan; Jiang, Yanan; Yang, Huiling; Jin, Ge; Zhao, Mingyao; Dong, Ziming

doi:10.3892/ijo.2012.1398

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…ORMDL3 activates ATF6, increasing the transcription of cAMP response element responsive genes; thus, ORMDL3 may mediate its own expression via a positive feedback loop. In addition, Alternariol, a mycotoxin of Alternaria , increases cAMP response element binding protein binding to CREs 39 and this may be the mechanism by which Alternaria increases ORMDL3 expression.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease

Löser

Gregory

Zhang

et al. 2017

Journal of Allergy and Clinical Immunology

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BackgroundGenome-wide association studies have identified the ORM (yeast)-like protein isoform 3 (ORMDL3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma.ObjectiveWe sought to investigate in vivo the functional role of ORMDL3 in disease inception.MethodsAn Ormdl3-deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata was determined. An adeno-associated viral vector was also used to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 knockout mice.ResultsOrmdl3 knockout mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response, and ORMDL3 was found to play a critical role in driving the activating transcription factor 6–mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum–associated degradation pathway. In addition, ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen–induced allergic airways disease.ConclusionsThis study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.

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Section: Discussionmentioning

confidence: 99%

Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease

Löser

Gregory

Zhang

et al. 2017

Journal of Allergy and Clinical Immunology

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“…Although this process has been known for decades, the regulation of PKA translocation is not fully understood. Some previous works indicated that failure of PKA catalytic subunit translocation largely impairs CREB phosphorylation [ 46 ]. Our results are consistent with the fact that translocation of the PKA-Cα subunit into the nucleus is required for CREB phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression

et al. 2014

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The ability to metastasize is a hallmark of malignant tumors, and metastasis is the principal cause of death of cancer patients. The High Mobility Group Box-1 (HMGB1) is a multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Our current study demonstrated a novel mechanism of HMGB1 in the regulation of cancer cell actin polymerization, cell skeleton formation, cancer cell motility and metastasis. We found that knockdown of HMGB1 in human lung cancer A549 cells significantly increased cell β-actin polymerization, cell skeleton formation, cancer cell migration and invasion in vitro, as well as metastasis in vivo. And this increase could be inhibited by treatment of HMGB1 knockdown cells with recombinant human HMGB1. Further studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit. This reduces nWASP mRNA transcription and expression, further impairing cancer cell motility. Our findings on the novel mechanism underlying the HMGB1 anti-metastatic effect on cancer provides significant insight into the understanding of the nature of HMGB1 in cancer invasion and metastasis, further serving as key information for utilization of HMGB1 and its regulated downstream components as new targets for cancer therapy.

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“…It is well-established that the POLB gene contains a CRE site in its core promoter essential for full promoter activity (Englander & Wilson, 1990;Widen et al, 1988;Yamaguchi et al, 1994). Moreover, previous studies have shown that POLB expression is stimulated in a CREB-dependent manner in response to DNA damaging agents in mammalian cell lines (He et al, 2003;Kedar et al, 1991;Narayan et al, 1995Narayan et al, , 1996Wang et al, 2001;Zhao et al, 2012). However, in primary cortical neurons many previously investigated stimuli, which alter APE1 in a CREB-mediated way, do not appear to affect POLB expression notably.…”

Section: Discussionmentioning

confidence: 99%

The role of aging and brain‐derived neurotrophic factor signaling in expression of base excision repair genes in the human brain

et al. 2023

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DNA damage is a central contributor to the aging process. In the brain, a major threat to the DNA is the considerable amount of reactive oxygen species produced, which can inflict oxidative DNA damage. This type of damage is removed by the base excision repair (BER) pathway, an essential DNA repair mechanism, which contributes to genome stability in the brain. Despite the crucial role of the BER pathway, insights into how this pathway is affected by aging in the human brain and the underlying regulatory mechanisms are very limited. By microarray analysis of four cortical brain regions from humans aged 20–99 years (n = 57), we show that the expression of core BER genes is largely downregulated during aging across brain regions. Moreover, we find that expression of many BER genes correlates positively with the expression of the neurotrophin brain‐derived neurotrophic factor (BDNF) in the human brain. In line with this, we identify binding sites for the BDNF‐activated transcription factor, cyclic‐AMP response element‐binding protein (CREB), in the promoter of most BER genes and confirm the ability of BDNF to regulate several BER genes by BDNF treatment of mouse primary hippocampal neurons. Together, these findings uncover the transcriptional landscape of BER genes during aging of the brain and suggest BDNF as an important regulator of BER in the human brain.

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Alternariol induces DNA polymerase β expression through the PKA-CREB signaling pathway

Cited by 5 publications

References 26 publications

Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease

Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease

High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression

The role of aging and brain‐derived neurotrophic factor signaling in expression of base excision repair genes in the human brain

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