Expression of genes in the TGF-β signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice

Guo, Jinpeng; Sartor, Maureen A.; Karyala, Saikumar; Medvedovic, Mario; Kann, Simone; Puga, Alvaro; Ryan, Patrick T.; Tomlinson, Craig R.

doi:10.1016/j.taap.2003.09.002

Cited by 92 publications

(73 citation statements)

References 48 publications

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“…Total RNA was isolated as described above for microarray analysis from each independent biological replicate (n ϭ 3 per condition). Microarray experiments were carried out essentially as previously described (41,42) with minor modifications. The Operon Array-Ready mouse genome oligonucleotide set consisting of 31,769 optimized 70-mer oligonucleotides was used to make microarrays (Qiagen).…”

Section: ϫ(⌬⌬Ct)mentioning

confidence: 99%

“…Data normalization was performed in two steps for each microarray separately (41,42). First, background adjusted intensities were log-transformed and the differences (M) and averages (A) of log-transformed values were calculated as M ϭ log 2 (X1) Ϫ log 2 (X2) and A ϭ [log 2 (X1) ϩ log 2 (X2)]/2, where X1 and X2 denote the Cy5 and Cy3 intensities, respectively.…”

Section: ϫ(⌬⌬Ct)mentioning

confidence: 99%

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BACH1 Is a Specific Repressor of HMOX1 That Is Inactivated by Arsenite

Reichard

Sartor

Puga

2008

Journal of Biological Chemistry

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Intracellular heme is a redox active molecule that can be detrimental to cells at high concentrations or under oxidizing conditions. To prevent accumulation, the inducible enzyme heme oxygenase-1 (HMOX1) catalyzes degradation of heme. In the absence of elevated intracellular heme or oxidative stress, the basic region leucine zipper transcriptional regulator BACH1 binds HMOX1 antioxidant response elements and represses transcription. Conversely, increased intracellular heme or sulfhydryl oxidation inactivate BACH1, permitting transcriptional induction of HMOX1. Here, we investigate the effect of BACH1 inactivation on the induction of HMOX1 and as a mechanism for broader gene induction. We show that BACH1 is inactivated at low micromolar arsenite concentrations and that BACH1 inactivation is necessary and sufficient for transcriptional induction of HMOX1. Because BACH1 is thought to interact with antioxidant response element motifs, we further examined the role of BACH1 as a regulator of inducible antioxidant gene expression by assessing the global profile of gene expression following BACH1 knockdown using small interfering RNA. The loss of BACH1 function in human keratinocytes results almost exclusively in HMOX1 induction, suggesting that BACH1 may function as a rheostat regulating levels of intracellular free heme. Heme oxygenase (HMOX)2 catalyzes the rate-limiting step of heme metabolism releasing carbon monoxide, iron, and biliverdin as products (1). Two heme oxygenase isoforms participate in heme metabolism: the inducible isoform heme oxygenase-1 (HMOX1) and the constitutive isoform heme oxygenase-2 (HMOX2). A third reported isoform, heme oxygenase-3, is considered to be a pseudogene processed from the HMOX2 transcript (2). HMOX1 induction is triggered by numerous forms of cellular stress, including transition metals (3, 4), heme and hemin (5-7), oxidants (8, 9), heat shock (10, 11), and hypoxia (12). In addition to metabolizing heme, HMOX1 reportedly protects against oxidative stress, a characteristic common to many HMOX1 inducers (13). The precise cytoprotective benefit of HMOX1 is unclear because HMOX1 itself does not directly catalyze an antioxidant reaction; however, removal of intracellular heme may be indirectly protective because (i) free intracellular heme is redox active; (ii) bilirubin, the product of biliverdin reduction, is an effective antioxidant; and (iii) iron released by heme degradation rapidly induces ferritin (14, 15).Arsenite, the trivalent form of inorganic arsenic, is an environmental contaminant of major concern and a potent inducer of oxidative stress. Many of the effects of arsenite are attributable to its affinity for soft nucleophiles, particularly cysteine residues in glutathione and proteins (16). Arsenite rapidly oxidizes glutathione, thereby disrupting intracellular redox status (17), and forms covalent adducts with redox-sensitive protein sulfhydryls leading to protein dysfunction. In response to oxidative stress, such as that mediated by arsenite, cells induce a battery of p...

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Section: ϫ(⌬⌬Ct)mentioning

confidence: 99%

Section: ϫ(⌬⌬Ct)mentioning

confidence: 99%

BACH1 Is a Specific Repressor of HMOX1 That Is Inactivated by Arsenite

Reichard

Sartor

Puga

2008

Journal of Biological Chemistry

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show abstract

“…Data normalization was performed in two steps for each microarray separately [15][16][17]. First, background adjusted intensities were log-transformed and the differences (R) and averages (A) of log-transformed values were calculated as R = log 2 (X1) − log 2 (X2) and A = [log 2 (X1) + log 2 (X2)]/2, where X1 and X2 denote the Cy5 and Cy3 intensities after subtracting local backgrounds, respectively.…”

Section: Data Normalization and Analysismentioning

confidence: 99%

MicroRNAs and regeneration: Let-7 members as potential regulators of dedifferentiation in lens and inner ear hair cell regeneration of the adult newt

Tsonis

Call

Grogg

et al. 2007

Biochemical and Biophysical Research Communications

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“…In vSMCs, TGF-␤ and BMP have been shown to promote the contractile phenotype and inhibit switching to the synthetic phenotype (20). Both TGF-␤s and BMPs inhibit vSMC proliferation and migration and increase contractile vSMC gene expression (16,20,22). Loss-of-function mutations of the genes encoding receptors of TGF-␤s and BMPs have been linked to vascular disorders, such as idiopathic PAH (IPAH) and hereditary hemorrhagic telangiectasia (41).…”

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confidence: 99%