ATF3, a Hub of the Cellular Adaptive-Response Network, in the Pathogenesis of Diseases: Is Modulation of Inflammation a Unifying Component?

Hai, Tsonwin; Wolford, Christopher C.; Chang, Yi-Seok

doi:10.3727/105221610x12819686555015

Cited by 284 publications

(348 citation statements)

References 71 publications

(2 reference statements)

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“…A particularly sensitive marker is activating transcription factor 3 (ATF3), a host defense transcription factor (22). We used ATF3 immunolabeling to determine if damage in the pancreas of either cerulein-treated or PKC animals caused an injury response in afferents of celiac, nodose, and T9-T12 dorsal root ganglia (DRG) (22)(23)(24)(25). Whereas vehicle-treated mice lacked ATF3 expression in all ganglia, cerulein-treated mice showed a few positive cells in all ganglia examined.…”

Section: Resultsmentioning

confidence: 99%

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Saloman

Albers

et al. 2016

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

272

243

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro-and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.sensory neuron | pancreatic ductal adenocarcinoma | tumorigenesis | inflammation | PanIN P ancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a median survival of ∼6 mo from diagnosis (National Cancer Institute). A number of unique features distinguish PDAC from other carcinomas, but the most striking is the exuberant desmoplastic infiltrate within tumors. This compartment exhibits an array of cell types, including activated myofibroblasts and myeloid-derived cells. Indeed, this inflammatory infiltrate is present at the inception of neoplasia and accumulates at a near exponential rate during progression to carcinoma and tumor formation. It provides a complex balance of pro-and antitumorigenic signals to neoplastic cells (and also to each other) that is a focus of intense investigation. The pancreas tumor microenvironment has been studied previously, but new tools [genetically engineered mouse models (GEMs) that faithfully recapitulate the salient features of human PDAC] now allow for a careful dissection of the stroma. Using these models, we showed that generalized inflammation is required for the development of precancerous pancreatic intraepithelial neoplasias (1) and that Hedgehog-dependent stromal elements, including activated myofibroblasts, serve to constrain tumor growth and spread (2). Other cellular components of the pancreatic inflammatory str...

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Section: Resultsmentioning

confidence: 99%

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Saloman

Albers

et al. 2016

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

272

243

View full text Add to dashboard Cite

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“…ATF3 is a transcription factor from the ATF/CREB family 5. Overpowering evidence proved that ATF3 translated by an immediate early gene and its expression is weak in various cells.…”

Section: Introductionmentioning

confidence: 99%

Transcription factor ATF3 mediates the radioresistance of breast cancer

Zhao

Sun

et al. 2018

J Cellular Molecular Medi

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This study was designed to research the influence of activating transcription factor 3 (ATF3) on the radioresistance of breast cancer. ATF3 expression was measured by qRT‐PCR and immunohistochemistry. Cancerous cell lines were cultured in vitro, and the expression of ATF3 was gauged by both qRT‐PCR and Western blot before and after the radiation therapy. Cellular cycle and apoptosis were analysed by flow cytometry. Changes in the expression of corresponding proteins in the downstream pathways were identified by Western blot. Tumour xenograft was used to evaluate the effect of ATF3 in vivo. ATF3 was observed stronger in breast cancer tissues and cells. After radiation therapy, the expression of ATF3 in breast cancer cells was up‐regulated. Silencing ATF3 could promote G2/M phase block, facilitate cell apoptosis and decrease clonogenic survival rate. The overexpression of ATF3 could curb G2/M‐phase block, cell apoptosis and increase clonogenic survival rate. Overexpression ATF3 could increase radioresistance by up‐regulating the level of phosphorylation of Akt in the PI3K/Akt signalling pathway. Radioresistance of breast cancer cells could be alleviated by inhibiting the PI3K/Akt signalling pathway. ATF3 could also promote radioresistance in vivo. ATF3 gene was able to promote radioresistance of breast cancer cells.

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“…Its protein product, ATF3, modulates the inflammatory response to these stimuli [1]. ATF3 downregulates inflammatory markers in hearts exposed to aortic banding-induced pressure overload [2], and in epithelial cells exposed to gram-negative bacteria [3].…”

Section: Introductionmentioning

confidence: 99%

Activating transcription factor 3 regulates chemokine expression in contracting C2C12 myotubes and in mouse skeletal muscle after eccentric exercise

Fernández‐Verdejo

Vanwynsberghe

Hai

et al. 2017

Biochemical and Biophysical Research Communications

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a b s t r a c tActivating transcription factor (ATF) 3 regulates chemokine expression in various cell types and tissues. Herein, we studied this regulation in contracting muscle cells in vitro, and in skeletal muscle after muscle-damaging exercise in vivo. C 2 C 12 myotubes with normal or low ATF3 levels (atf3_siRNA) were electrically stimulated (EPS). Also, ATF3-knockout (ATF3-KO) and control mice ran downhill until exhaustion, and muscles were analyzed post-exercise. EPS increased ATF3 levels in myotubes (P < 0.01). Chemokine C-C motif ligand (ccl) 2 mRNA increased post-EPS, but atf3_siRNA attenuated the response (P < 0.05). Atf3_siRNA up-regulated ccl6 basal mRNA, and down-regulated ccl9 and chemokine C-X-C motif ligand (cxcl) 1 basal mRNAs. Post-exercise, ATF3-KO mice showed exacerbated mRNA levels of ccl6 and ccl9 in soleus (P < 0.05), and similar trends were observed for ccl2 and interleukin (il) 1b (P < 0.09). In quadriceps, il6 mRNA level increased only in ATF3-KO (P < 0.05), and cxcl1 mRNA showed a similar trend (P ¼ 0.082). Cluster of differentiation-68 (cd68) mRNA, a macrophage marker, increased in quadriceps and soleus independently of genotype (P < 0.001). Our data demonstrate that ATF3 regulates chemokine expression in muscle cells in vitro and skeletal muscle in vivo, but the regulation differs in each model. Cells other than myofibers may thus participate in the response observed in skeletal muscle. Our results also indicate that ATF3-independent mechanisms would regulate macrophage infiltration upon muscledamaging exercise. The implications of chemokine regulation in skeletal muscle remain to be determined.

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ATF3, a Hub of the Cellular Adaptive-Response Network, in the Pathogenesis of Diseases: Is Modulation of Inflammation a Unifying Component?

Cited by 284 publications

References 71 publications

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Transcription factor ATF3 mediates the radioresistance of breast cancer

Activating transcription factor 3 regulates chemokine expression in contracting C2C12 myotubes and in mouse skeletal muscle after eccentric exercise

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