Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery

Haridas, Valsala; Hanausek, Margaret; Nishimura, Goshi; Soehnge, Holly; Gaikwad, Amos; Naróg, Maciej; Spears, Erick; Zoltaszek, Robert; Wałaszek, Zbigniew; Gutterman, Jordan U.

doi:10.1172/jci18699

Cited by 39 publications

(35 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The results reported in this paper also support a link between avicins' ability to regulate cellular stress [6], [20], as well as organismal stress via the glucocorticoid axis. To get an idea of avicin's effects in a more physiological system we chose to study its effect on the process of adipocyte differentiation.…”

Section: Discussionsupporting

confidence: 78%

The Anticancer Plant Triterpenoid, Avicin D, Regulates Glucocorticoid Receptor Signaling: Implications for Cellular Metabolism

Haridas

Kitchen

et al. 2011

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Avicins, a family of apoptotic triterpene electrophiles, are known to regulate cellular metabolism and energy homeostasis, by targeting the mitochondria. Having evolved from “ancient hopanoids,” avicins bear a structural resemblance with glucocorticoids (GCs), which are the endogenous regulators of metabolism and energy balance. These structural and functional similarities prompted us to compare the mode of action of avicin D with dexamethasone (Dex), a prototypical GC. Using cold competition assay, we show that Avicin D competes with Dex for binding to the GC receptor (GR), leading to its nuclear translocation. In contrast to Dex, avicin-induced nuclear translocation of GR does not result in transcriptional activation of GC-dependent genes. Instead we observe a decrease in the expression of GC-dependent metabolic proteins such as PEPCK and FASN. However, like Dex, avicin D treatment does induce a transrepressive effect on the pro-inflammatory transcription factor NF-κB. While avicin's ability to inhibit NF-κB and its downstream targets appear to be GR-dependent, its pro-apoptotic effects were independent of GR expression. Using various deletion mutants of GR, we demonstrate the requirement of both the DNA and ligand binding domains of GR in mediating avicin D's transrepressive effects. Modeling of avicin-GR interaction revealed that avicin molecule binds only to the antagonist confirmation of GR. These findings suggest that avicin D has properties of being a selective GR modulator that separates transactivation from transrepression. Since the gene-activating properties of GR are mainly linked to its metabolic effects, and the negative interference with the activity of transcription factors to its anti-inflammatory and immune suppressive effects, the identification of such a dissociated GR ligand could have great potential for therapeutic use.

show abstract

Section: Discussionsupporting

confidence: 78%

The Anticancer Plant Triterpenoid, Avicin D, Regulates Glucocorticoid Receptor Signaling: Implications for Cellular Metabolism

Haridas

Kitchen

et al. 2011

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…Triterpenoids are electrophiles (48) that undergo Michael reaction and inactivate Keap1 (19), thus allowing Nrf2 to avoid ubiquitination and proteasome degradation, and thereby producing elevated Nrf2 signaling. CDDO (1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl)) is a triterpenoid that results in robust Nrf2 activation.…”

Section: Nrf2 and Radiation-induced Intestinal Injurymentioning

confidence: 99%

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

et al. 2018

View full text Add to dashboard Cite

The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post-transcriptional regulation entails ubiquitination followed by proteasome-dependent degradation. Additionally, Nrf2-mediated gene expression is subject to negative regulation by ATF3, Bach1 and cMyc. Nrf2-mediated gene expression is an important regulator of a cell’s response to radiation. Although a majority of studies have shown that Nrf2 deficient cells are radiosensitized and Nrf2 over expression confers radioresistance, Nrf2’s role in mediating the radiation response of crypt cells is controversial. The Nrf2 activator CDDO attenuates radiation-mediated crypt injury, whereas intestinal crypts in Nrf2 null mice are radiation resistant. Further investigation is needed in order to define the relationship between Nrf2 and radiation sensitivity in Lgr5+ and Bmi1+ cells that regulate regeneration of crypt stem cells. In hematopoietic compartments Nrf2 promotes the survival of irradiated osteoblasts that support long-term hematopoietic stem cell (LT-HSC) niches. Loss of Nrf2 in LT-HSCs increases stem cell intrinsic radiosensitivity, with the consequence of lowering the LD5030. An Nrf2 deficiency drives LT-HSCs from a quiescent to a proliferative state. This results in hematopoietic exhaustion and reduced engraftment after myoablative irradiation. The question of whether induction of Nrf2 in LT-HSC enhances hematopoietic reconstitution after bone marrow transplantation is not yet resolved. Irradiation of the lung induces pulmonary pneumonitis and fibrosis. Loss of Nrf2 promotes TGF-β/Smad signaling that induces ATF3 suppression of Nrf2-mediated target gene expression. This, in turn, results in elevated reactive oxygen species (ROS) and isolevuglandin adduction of protein that impairs collagen degradation, and may contribute to radiation-induced chronic cell injury. Loss of Nrf2 impairs ΔNp63 stem/progenitor cell mobilization after irradiation, while promoting alveolar type 2 cell epithelial-mesenchymal transitions into myofibroblasts. These studies identify Nrf2 as an important factor in the radiation response of normal tissue.

show abstract

“…Avicin G inhibited the TNF‐induced NF‐κB DNA‐binding activity, which was suppressed by addition of the thiol‐specific reducing agent dithiothreitiol (DTT) 86. Avicins has been known to induce phase 2 detoxification enzymes, such as HO‐1 and NQO1, via activation of Nrf2 in human hepatoma HepG2 cells 87. Pretreatment of cells with DTT almost completely blocked the effect of avicin D. Avicins activate the paradigmatic redox‐response transcriptional activator, OxyR of Escherichia coli , which protects bacterial cells against oxidative or nitrosative stress 87.…”

Section: Chemopreventive Agents Targeting Redox‐responsive Transcriptmentioning

confidence: 99%

Transcriptional regulation via cysteine thiol modification: A novel molecular strategy for chemoprevention and cytoprotection

Surh

2006

Molecular Carcinogenesis

102

View full text Add to dashboard Cite

Chemoprevention refers to the use of defined nontoxic chemical regimens to inhibit, reverse, or retard the process of multistage carcinogenesis that involves multiple signal transduction events. Identification of signaling molecules associated with carcinogenesis as prime targets of chemopreventive agents has become an area of great interest. Recent studies have implicated cysteine thiols present in various transcription factors, such as NF-kappaB, AP-1, and p53 as redox sensors in transcriptional regulation of many genes essential for maintaining cellular homeostasis. Some chemopreventive and cytoprotective agents have been found to target cysteine thiols present in key transcription factors or their regulators, thereby suppressing aberrant over-activation of carcinogenic signal transduction or restoring/normalizing or even potentiating cellular defense signaling. The focus of this review is the oxidation or covalent modification of thiol groups present in key representative redox-sensitive transcription factors and their regulating molecules as a unique strategy for molecular target-based chemoprevention and cytoprotection.

show abstract

Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery

Cited by 39 publications

References 50 publications

The Anticancer Plant Triterpenoid, Avicin D, Regulates Glucocorticoid Receptor Signaling: Implications for Cellular Metabolism

The Anticancer Plant Triterpenoid, Avicin D, Regulates Glucocorticoid Receptor Signaling: Implications for Cellular Metabolism

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

Transcriptional regulation via cysteine thiol modification: A novel molecular strategy for chemoprevention and cytoprotection

Contact Info

Product

Resources

About