Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis

The heart exhibits incredible plasticity in response to both environmental and genetic alterations that affect workload. Over the course of development, or in response to physiological or pathological stimuli, the heart responds to fluctuations in workload by hypertrophic growth primarily by individual cardiac myocytes growing in size. Cardiac hypertrophy is associated with an increase in protein synthesis, which must coordinate with protein folding and degradation to allow for homeostatic growth without affecting the functional integrity of cardiac myocytes (i.e., proteostasis). This increase in the protein folding demand in the growing cardiac myocyte activates the transcription factor, ATF6 (activating transcription factor 6α, an inducer of genes that restore proteostasis. Previously, ATF6 has been shown to induce ER-targeted proteins functioning primarily to enhance ER protein folding and degradation. More recent studies, however, have illuminated adaptive roles for ATF6 functioning outside of the ER by inducing non-canonical targets in a stimulus-specific manner. This unique ability of ATF6 to act as an initial adaptive responder has bolstered an enthusiasm for identifying small molecule activators of ATF6 and similar proteostasis-based therapeutics.

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Sledgehammer to Scalpel: Broad Challenges to the Heart and Other Tissues Yield Specific Cellular Responses via Transcriptional Regulation of the ER-Stress Master Regulator ATF6α

International Journal of Molecular Sciences ◽

10.3390/ijms21031134 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1134 ◽

Cited By ~ 1

Author(s):

Winston T. Stauffer ◽

Adrian Arrieta ◽

Erik A. Blackwood ◽

Christopher C. Glembotski

Keyword(s):

Transcription Factor ◽

Protein Folding ◽

Er Stress ◽

Molecular Mechanisms ◽

Transmembrane Protein ◽

Fine Tuning ◽

Cellular Functions ◽

Similar Mode ◽

Activating Transcription Factor ◽

Activating Transcription Factor 6Α

There are more than 2000 transcription factors in eukaryotes, many of which are subject to complex mechanisms fine-tuning their activity and their transcriptional programs to meet the vast array of conditions under which cells must adapt to thrive and survive. For example, conditions that impair protein folding in the endoplasmic reticulum (ER), sometimes called ER stress, elicit the relocation of the ER-transmembrane protein, activating transcription factor 6α (ATF6α), to the Golgi, where it is proteolytically cleaved. This generates a fragment of ATF6α that translocates to the nucleus, where it regulates numerous genes that restore ER protein-folding capacity but is degraded soon after. Thus, upon ER stress, ATF6α is converted from a stable, transmembrane protein, to a rapidly degraded, nuclear protein that is a potent transcription factor. This review focuses on the molecular mechanisms governing ATF6α location, activity, and stability, as well as the transcriptional programs ATF6α regulates, whether canonical genes that restore ER protein-folding or unexpected, non-canonical genes affecting cellular functions beyond the ER. Moreover, we will review fascinating roles for an ATF6α isoform, ATF6β, which has a similar mode of activation but, unlike ATF6α, is a long-lived, weak transcription factor that may moderate the genetic effects of ATF6α.

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C-myc protooncogene modulates cardiac hypertrophic growth in transgenic mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.2.h590 ◽

1992 ◽

Vol 262 (2) ◽

pp. H590-H597 ◽

Cited By ~ 2

Author(s):

R. J. Robbins ◽

J. L. Swain

Keyword(s):

Transgenic Mice ◽

Cardiac Myocytes ◽

Cardiac Myocyte ◽

Fold Increase ◽

Cardiac Mass ◽

Hypertrophic Growth ◽

Basal Expression ◽

Pharmacological Stimulation ◽

Beta Adrenergic Agonist

Protooncogenes such as c-myc have been implicated in the transduction of growth signals in the cardiac myocyte. We examined whether increases in c-myc expression occur in murine heart in vivo as a generalized response to the pharmacological stimulation of myocyte growth. Both triiodothyronine (T3) and the beta-adrenergic agonist isoproterenol were demonstrated to induce a rapid and transient increase in cardiac c-myc mRNA abundance, which preceded an increase in cardiac mass. We then examined whether myocyte growth could be modulated by selectively altering cardiac c-myc expression. The model system used was a strain of transgenic mice exhibiting a 20-fold increase in cardiac c-myc expression. Although in nontransgenic mice the administration of T3 and isoproterenol resulted in similar increases in cardiac mass, in transgenic mice the degree of myocardial growth induced with T3 was significantly greater than that induced with isoproterenol (P less than 0.001). This study demonstrates that increasing the basal expression of c-myc in cardiac myocytes alters the growth response of the heart in vivo to certain hypertrophic stimuli and implicates the c-myc protooncogene in the transduction of selective hypertrophic growth signals in differentiated cardiac myocytes.

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The activating transcription factor 2: an influencer of cancer progression

Mutagenesis ◽

10.1093/mutage/gez041 ◽

2019 ◽

Vol 34 (5-6) ◽

pp. 375-389 ◽

Cited By ~ 2

Author(s):

Kerstin Huebner ◽

Jan Procházka ◽

Ana C Monteiro ◽

Vijayalakshmi Mahadevan ◽

Regine Schneider-Stock

Keyword(s):

Pancreatic Cancer ◽

Transcription Factor ◽

3D Structure ◽

Genetic Alterations ◽

Tumour Suppressor Genes ◽

Subcellular Localisation ◽

Dependent Manner ◽

Continuous Increase ◽

Mesenchymal Transition ◽

Activating Transcription Factor

Abstract In contrast to the continuous increase in survival rates for many cancer entities, colorectal cancer (CRC) and pancreatic cancer are predicted to be ranked among the top 3 cancer-related deaths in the European Union by 2025. Especially, fighting metastasis still constitutes an obstacle to be overcome in CRC and pancreatic cancer. As described by Fearon and Vogelstein, the development of CRC is based on sequential mutations leading to the activation of proto-oncogenes and the inactivation of tumour suppressor genes. In pancreatic cancer, genetic alterations also attribute to tumour development and progression. Recent findings have identified new potentially important transcription factors in CRC, among those the activating transcription factor 2 (ATF2). ATF2 is a basic leucine zipper protein and is involved in physiological and developmental processes, as well as in tumorigenesis. The mutation burden of ATF2 in CRC and pancreatic cancer is rather negligible; however, previous studies in other tumours indicated that ATF2 expression level and subcellular localisation impact tumour progression and patient prognosis. In a tissue- and stimulus-dependent manner, ATF2 is activated by upstream kinases, dimerises and induces target gene expression. Dependent on its dimerisation partner, ATF2 homodimers or heterodimers bind to cAMP-response elements or activator protein 1 consensus motifs. Pioneering work has been performed in melanoma in which the dual role of ATF2 is best understood. Even though there is increasing interest in ATF2 recently, only little is known about its involvement in CRC and pancreatic cancer. In this review, we summarise the current understanding of the underestimated ‘cancer gene chameleon’ ATF2 in apoptosis, epithelial-to-mesenchymal transition and microRNA regulation and highlight its functions in CRC and pancreatic cancer. We further provide a novel ATF2 3D structure with key phosphorylation sites and an updated overview of all so-far available mouse models to study ATF2 in vivo.

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A growth factor for cardiac myocytes is produced by cardiac nonmyocytes.

Cell Regulation ◽

10.1091/mbc.2.12.1081 ◽

1991 ◽

Vol 2 (12) ◽

pp. 1081-1095 ◽

Cited By ~ 106

Author(s):

C S Long ◽

C J Henrich ◽

P C Simpson

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Cardiac Myocytes ◽

Transforming Growth Factor Beta ◽

Cardiac Myocyte ◽

Transforming Growth Factor ◽

Tnf Alpha ◽

Dependent Manner ◽

Tgf Beta ◽

Hypertrophic Growth

Cardiac nonmyocytes, primarily fibroblasts, surround cardiac myocytes in vivo. We examined whether nonmyocytes could modulate myocyte growth by production of one or more growth factors. Cardiac myocyte hypertrophic growth was stimulated in cultures with increasing numbers of cardiac nonmyocytes. This effect of nonmyocytes on myocyte size was reproduced by serum-free medium conditioned by the cardiac nonmyocytes. The majority of the nonmyocyte-derived myocyte growth-promoting activity bound to heparin-Sepharose and was eluted with 0.75 M NaCl. Several known polypeptide growth factors found recently in cardiac tissue, namely acidic fibroblast growth factor (aFGF), basic FGF (bFGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF alpha), and transforming growth factor beta 1 (TGF beta 1), also caused hypertrophy of cardiac myocytes in a dose-dependent manner. However, the nonmyocyte-derived growth factor (tentatively named NMDGF) could be distinguished from these other growth factors by different heparin-Sepharose binding profiles (TNF alpha, aFGF, bFGF, and TGF beta 1) by neutralizing growth factor-specific antisera (PDGF, TNF alpha, aFGF, bFGF, and TGF beta 1), by the failure of NMDGF to stimulate phosphatidylinositol hydrolysis (PDGF and TGF beta 1), and, finally, by the apparent molecular weight of NMDGF (45-50 kDa). This nonmyocyte-derived heparin-binding growth factor may represent a novel paracrine growth mechanism in myocardium.

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Adenylyl Cyclase Type VI Gene Transfer Reduces Phospholamban Expression in Cardiac Myocytes via Activating Transcription Factor 3

Journal of Biological Chemistry ◽

10.1074/jbc.m405701200 ◽

2004 ◽

Vol 279 (37) ◽

pp. 38797-38802 ◽

Cited By ~ 28

Author(s):

Mei Hua Gao ◽

Tong Tang ◽

Tracy Guo ◽

Shu Qiang Sun ◽

James R. Feramisco ◽

...

Keyword(s):

Transcription Factor ◽

Gene Transfer ◽

Adenylyl Cyclase ◽

Cardiac Myocytes ◽

Activating Transcription Factor 3 ◽

Activating Transcription Factor ◽

Transcription Factor 3

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Abstract 4505: Activating transcription factor-6α dependent regulation of Rheb-mTOR and Notch signaling contributes to chemoresistance in osteosarcoma

10.1158/1538-7445.am2017-4505 ◽

2017 ◽

Author(s):

Suma Yarapureddy ◽

Pooja Hingorani ◽

Saravana Kumar ◽

Omar Asad ◽

Jazmine Abril ◽

...

Keyword(s):

Transcription Factor ◽

Notch Signaling ◽

Activating Transcription Factor ◽

Activating Transcription Factor 6Α

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ER stress signaling has an activating transcription factor 6α (ATF6)-dependent “off-switch”

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.002121 ◽

2018 ◽

Vol 293 (47) ◽

pp. 18270-18284 ◽

Cited By ~ 18

Author(s):

Franziska Walter ◽

Aisling O'Brien ◽

Caoimhín G. Concannon ◽

Heiko Düssmann ◽

Jochen H. M. Prehn

Keyword(s):

Transcription Factor ◽

Er Stress ◽

Neuroblastoma Cells ◽

Stress Signaling ◽

Signaling Proteins ◽

Protein Levels ◽

Activating Transcription Factor ◽

Screening Platform ◽

The Unfolded Protein Response ◽

Activating Transcription Factor 6Α

In response to an accumulation of unfolded proteins in the endoplasmic reticulum (ER) lumen, three ER transmembrane signaling proteins, inositol-requiring enzyme 1 (IRE1), PRKR-like ER kinase (PERK), and activating transcription factor 6α (ATF6α), are activated. These proteins initiate a signaling and transcriptional network termed the unfolded protein response (UPR), which re-establishes cellular proteostasis. When this restoration fails, however, cells undergo apoptosis. To investigate cross-talk between these different UPR enzymes, here we developed a high-content live cell screening platform to image fluorescent UPR-reporter cell lines derived from human SH-SY5Y neuroblastoma cells in which different ER stress signaling proteins were silenced through lentivirus-delivered shRNA constructs. We observed that loss of ATF6 expression results in uncontrolled IRE1-reporter activity and increases X box–binding protein 1 (XBP1) splicing. Transient increases in both IRE1 mRNA and IRE1 protein levels were observed in response to ER stress, suggesting that IRE1 up-regulation is a general feature of ER stress signaling and was further increased in cells lacking ATF6 expression. Moreover, overexpression of the transcriptionally active N-terminal domain of ATF6 reversed the increases in IRE1 levels. Furthermore, inhibition of IRE1 kinase activity or of downstream JNK activity prevented an increase in IRE1 levels during ER stress, suggesting that IRE1 transcription is regulated through a positive feed-forward loop. Collectively, our results indicate that from the moment of activation, IRE1 signaling during ER stress has an ATF6-dependent “off-switch.”

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