Bach1 inhibits oxidative stress–induced cellular senescence by impeding p53 function on chromatin

Dohi, Yoshihiro; Ikura, Tsuyoshi; Hoshikawa, Yutaka; Katoh, Yohei; Ota, Kyoko; Nakanome, Ayako; Muto, Akihiko; Omura, Shinji; Ohta, Tsutomu; Ito, Akihiro; Yoshida, Minoru; Noda, Tetsuo; Igarashi, Kazuhiko

doi:10.1038/nsmb.1516

Cited by 89 publications

(112 citation statements)

References 44 publications

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“…These apparently conflicting results are reconciled by the fact that even under normal culture conditions, cells are exposed to oxidative stress due to the presence of ϳ20% oxygen in the atmosphere (32). We hypothesize that the levels of Bach1 were sufficient to inhibit HO-1 induction in response to oxidative stress.…”

Section: Discussionmentioning

confidence: 93%

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Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

Okada

Muto

Ogawa

et al. 2010

Journal of Biological Chemistry

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Bach1 is a member of the basic leucine zipper transcription factor family, and the Bach1/small Maf heterodimer specifically represses transcriptional activity directed by the Maf recognition element (MARE). Because Bach1 is a repressor of the oxidative stress response, we examined the function(s) of Bach1 in keratinocytes subjected to oxidative stress. Oxidative stress induced by H 2 O 2 led to an increase in MARE activity and expression of heme oxygenase-1 (HO-1), an inducible antioxidant defense enzyme. Bach1 depletion by small interfering RNAs or by deletion of Bach1 enhanced HO-1 expression in the absence of H 2 O 2 , indicating that Bach1 is a critical repressor of HO-1 in keratinocytes. Although Bach1-deficient or -reduced keratinocytes expressed higher levels of HO-1 than control cells in response to H 2 O 2 , Bach1 down-regulation did not attenuate the production of reactive oxygen species by H 2 O 2 . In contrast, Bach1 overexpression abolished HO-1 induction by H 2 O 2 , which led to increased reactive oxygen species accumulation. HO-1 was induced during keratinocyte differentiation, but MARE activity did not change during differentiation. Furthermore, Bach1 overexpression did not inhibit differentiation-associated induction of HO-1 expression, suggesting that HO-1 induction in differentiation is independent of Bach1. Thus, in response to oxidative stress, Bach1 regulates the oxidation state through the negative control of HO-1 expression prior to terminal keratinocyte differentiation. However, Bach1-mediated repression is negated during keratinocyte differentiation.Redox regulation is critical to cell survival, because cells cannot avoid endogenous reactive oxygen species (ROS) 2 that are generated as by-products of respiration (1). The skin is constantly exposed to harmful ROS that are generated by prooxidant agents in the environment, as well as by endogenous cellular oxidants. Thus, keratinocytes strongly and constitutively express ROS-detoxifying enzymes, including superoxide dismutase, catalase, glutathione peroxidase, and reductase, and contain substantial levels of the antioxidants tocopherol and ubiquinol (2, 3). Additionally, these cells possess an inducible defense system that includes heme oxygenase-1 (HO-1) (3-5). An imbalance between ROS and antioxidants can lead to the generation of high oxidant levels, which play a pivotal role in skin aging and disease (6).The transcription factor Bach1 is a repressor of the oxidative stress response in higher eukaryotes (7,8) and, together with its paralogue Bach2, constitutes a subfamily of the basic leucine zipper family of proteins. Bach1 forms heterodimers with the basic leucine zipper subfamily of small Maf proteins (i.e. MafF, MafG, and MafK), which bind the Maf recognition element (MARE) in the promoter regions of genes such as HO-1, NADP(H) quinone (oxido)reductase, and ␤-globin (7, 9, 10), and thereby repress transcription in the absence of oxidative stress. In the presence of oxidative stress, Bach1 is inactivated (11, 12), which allows tran...

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Section: Discussionmentioning

confidence: 93%

“…Bach1 binds to heme through its heme regulatory motif, which results in the loss of its repressor activity (52) and the induction of HO-1. In addition, Bach1 has recently been reported to inhibit oxidative stress-induced cellular senescence by impeding the function of p53 (32). Bach1 function may affect…”

Section: Discussionmentioning

confidence: 99%

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

Okada

Muto

Ogawa

et al. 2010

Journal of Biological Chemistry

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“…26 BACH1 inhibits p53-dependent premature cellular senescence in response to oxidative stress. 27 ZBTB2 was found to increase cell proliferation by repressing transcription of the p21 CIP1 gene, a well known p53 target gene. 28 HIC1 suppresses age-dependent development of cancer by mediating SIRT1-and p53-dependent apoptotic DNA damage responses.…”

Section: Discussionmentioning

confidence: 99%

POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) inhibits endothelial cell senescence through a p53 dependent pathway

Cho

Kim

et al. 2011

Cell Death Differ

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Vascular cell senescence, induced by the DNA damage response or inflammatory stress, contributes to age-associated vascular disease. Using complementary DNA microarray technology, we found that the level of POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is downregulated during endothelial cell (EC) senescence. PATZ1 may have an important role as a transcriptional repressor in chromatin remodeling and transcription regulation; however, the role of PATZ1 in EC senescence and vascular aging remains unidentified. Knockdown of PATZ1 in young cells accelerated premature EC senescence, which was confirmed by growth arrest, increased p53 protein level and senescence-associated b-galactosidase (SA-b-gal) activity, and repression of EC tube formation. In contrast, overexpression of PATZ1 in senescent cells reversed senescent phenotypes. Cellular senescence induced by PATZ1 knockdown in young cells was rescued by knockdown of p53, but not by knockdown of p16 INK4a . PATZ1 knockdown increased ROS levels, and pretreatment with N-acetylcysteine abolished EC senescence induced by PATZ1 knockdown. Notably, PATZ1 immunoreactivity was lower in ECs of atherosclerotic tissues than those of normal arteries in LDLR À/À mice, and immunoreactivity also decreased in ECs of old human arteries. These results suggest that PATZ1 may have an important role in the regulation of EC senescence through an ROS-mediated p53-dependent pathway and contribute to vascular diseases associated with aging.

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“…To understand whether BACH1 directly regulates RKIP expression by binding to its promoter region, we analyzed a region −3,000 bp upstream of the RKIP transcription start site (TSS) and identified three BACH1 (AP-1-like) binding motifs (TGAGCCA) (21) (Fig. 2A).…”

Section: Bach1 Negativelymentioning

confidence: 99%

“…One of the downstream targets inhibited by RKIP through let-7 is BACH1, a basic leucine zipper transcription factor that regulates oxidative stress and stress-induced senescence (21,22). BACH1 promotes metastasis of triple-negative breast cancers (TNBCs) but does not significantly affect primary tumor growth (23).…”

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confidence: 99%

Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions

Lee

Farquhar

et al. 2014

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

131

151

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The sources and consequences of nongenetic variability in metastatic progression are largely unknown. To address these questions, we characterized a transcriptional regulatory network for the metastasis suppressor Raf kinase inhibitory protein (RKIP). We previously showed that the transcription factor BACH1 is negatively regulated by RKIP and promotes breast cancer metastasis. Here we demonstrate that BACH1 acts in a double-negative (overall positive) feedback loop to inhibit RKIP transcription in breast cancer cells. BACH1 also negatively regulates its own transcription. Analysis of the BACH1 network reveals the existence of an inverse relationship between BACH1 and RKIP involving both monostable and bistable transitions that can potentially give rise to nongenetic variability. Single-cell analysis confirmed monostable and bistablelike behavior. Treatment with histone deacetylase inhibitors or depletion of the polycomb repressor enhancer of zeste homolog 2 altered relative RKIP and BACH1 levels in a manner consistent with a prometastatic state. Together, our results suggest that the mutually repressive relationship between metastatic regulators such as RKIP and BACH1 can play a key role in determining metastatic progression in cancer.ancer progression is an evolutionary process of variant cells competing to expand first locally and then distally within the human body. Ultimately, tumor evolution generates metastatic lesions that account for over 90% of cancer deaths (1). Whereas the requirement of heritably variant cells for tumor progression is undisputed, how they emerge is much less clear. Traditionally, genetic mutations causing oncogene activation or tumor suppressor loss were considered essential (2). However, accumulating evidence for tumor-promoting epigenetic, microenvironmental, and stochastic forms of heritable variation is challenging the traditional view (3, 4). Genetically identical tumor cells show highly variable responses to apoptosis-inducing ligands (5) and chemotherapeutic drugs (6, 7) attributable to cell-cell differences in gene expression and pathway activity. Tumor cells diversify in vitro (8) and in vivo (9) showing different levels of stem cell marker expression. However, the molecular mechanisms and interactions controlling such nongenetic forms of diversity are not fully known (10, 11).Multiple studies have implicated positive feedback loops in amplifying and maintaining stochastic fluctuations, creating heritable diversity in genetically homogenous cell populations (12, 13). This heritable nongenetic diversity then generates random subpopulations that can survive during various forms of environmental stress (14, 15), enabling subsequent evolutionary adaptation (16). Understanding how feedback loops and other network structures may affect nongenetic heterogeneity and contribute to metastatic cancer progression will be crucial for combating the disease (3, 10). However, the regulation of metastasis-related genes is incompletely understood, and the role of regulatory network-mediated n...

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Bach1 inhibits oxidative stress–induced cellular senescence by impeding p53 function on chromatin

Cited by 89 publications

References 44 publications

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) inhibits endothelial cell senescence through a p53 dependent pathway

Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions

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