Role of the Tumor Suppressor PTEN in Antioxidant Responsive Element-mediated Transcription and Associated Histone Modifications

Coordinated regulation of PI3-kinase (PI3K) and the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) plays a pivotal role in various cell functions. PTEN is deficient in many cancer cells, including Jurkat human leukemia. Here, we demonstrate that the status of PTEN determines cellular susceptibility to oxidative stress through antioxidant-responsive element (ARE)-mediated transcription of detoxification genes. We found that ferritin H transcription was robustly induced in tert-butylhydroquinone (t-BHQ)-treated Jurkat cells via an ARE, and it was due to PTEN deficiency. Chromatin immunoprecipitation assays revealed that p300/CREB-binding protein (CBP) histone acetyltransferases and Nrf2 recruitment to the ARE and Bach1 release were blocked by the PI3K inhibitor LY294002, along with the partial inhibition of Nrf2 nuclear accumulation. Furthermore, acetylations of histone H3 Lys9 and Lys18, and deacetylation of Lys14 were associated with the PI3K-dependent ARE activation. Consistently, PTEN restoration in Jurkat cells inhibited t-BHQ–mediated expression of ferritin H and another ARE-regulated gene NAD(P)H:quinone oxidoreductase 1. Conversely, PTEN knockdown in K562 cells enhanced the response to t-BHQ. The PTEN status under t-BHQ treatment affected hydrogen peroxide-mediated caspase-3 cleavage. The PI3K-dependent ferritin H induction was observed by treatment with other ARE-activating agents ethoxyquin and hemin. Collectively, the status of PTEN determines chromatin modifications leading to ARE activation.

Download Full-text

PIAS3 Interacts with ATF1 and Regulates the Human Ferritin H Gene through an Antioxidant-responsive Element

Journal of Biological Chemistry ◽

10.1074/jbc.m701477200 ◽

2007 ◽

Vol 282 (31) ◽

pp. 22335-22343 ◽

Cited By ~ 27

Author(s):

Kenta Iwasaki ◽

Kiros Hailemariam ◽

Yoshiaki Tsuji

Keyword(s):

H Gene ◽

Human Ferritin ◽

Responsive Element ◽

Ferritin H ◽

Antioxidant Responsive Element

Download Full-text

Hemin-Mediated Regulation of an Antioxidant-Responsive Element of the Human Ferritin H Gene and Role of Ref-1 during Erythroid Differentiation of K562 Cells

Molecular and Cellular Biology ◽

10.1128/mcb.26.7.2845-2856.2006 ◽

2006 ◽

Vol 26 (7) ◽

pp. 2845-2856 ◽

Cited By ~ 82

Author(s):

Kenta Iwasaki ◽

Elizabeth L. MacKenzie ◽

Kiros Hailemariam ◽

Kensuke Sakamoto ◽

Yoshiaki Tsuji

Keyword(s):

Transcription Factors ◽

Dna Binding ◽

K562 Cells ◽

Erythroid Differentiation ◽

Luciferase Reporter ◽

H Gene ◽

Human Ferritin ◽

Responsive Element ◽

Ferritin H ◽

Antioxidant Responsive Element

ABSTRACT An effective utilization of intracellular iron is a prerequisite for erythroid differentiation and hemoglobinization. Ferritin, consisting of 24 subunits of H and L, plays a crucial role in iron homeostasis. Here, we have found that the H subunit of the ferritin gene is activated at the transcriptional level during hemin-induced differentiation of K562 human erythroleukemic cells. Transfection of various 5′ regions of the human ferritin H gene fused to a luciferase reporter into K562 cells demonstrated that hemin activates ferritin H transcription through an antioxidant-responsive element (ARE) that is responsible for induction of a battery of phase II detoxification genes by oxidative stress. Gel retardation and chromatin immunoprecipitation assays demonstrated that hemin induced binding of cJun, JunD, FosB, and Nrf2 b-zip transcription factors to AP1 motifs of the ferritin H ARE, despite no significant change in expression levels or nuclear localization of these transcription factors. A Gal4-luciferase reporter assay did not show activation of these b-zip transcription factors after hemin treatment; however, redox factor 1 (Ref-1), which increases DNA binding of Jun/Fos family members via reduction of a conserved cysteine in their DNA binding domains, showed induced nuclear translocation after hemin treatment in K562 cells. Consistently, Ref-1 enhanced Nrf2 binding to the ARE and ferritin H transcription. Hemin also activated ARE sequences of other phase II genes, such as GSTpi and NQO1. Collectively, these results suggest that hemin activates the transcription of the ferritin H gene during K562 erythroid differentiation by Ref-1-mediated activation of these b-zip transcription factors to the ARE.

Download Full-text

The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)99004-6 ◽

1991 ◽

Vol 266 (18) ◽

pp. 11632-11639 ◽

Cited By ~ 9

Author(s):

T.H. Rushmore ◽

M.R. Morton ◽

C.B. Pickett

Keyword(s):

Oxidative Stress ◽

Functional Activity ◽

Consensus Sequence ◽

Responsive Element ◽

Antioxidant Responsive Element

Download Full-text

Acetylation of cAMP-responsive Element-binding Protein (CREB) by CREB-binding Protein Enhances CREB-dependent Transcription

Journal of Biological Chemistry ◽

10.1074/jbc.m300546200 ◽

2003 ◽

Vol 278 (18) ◽

pp. 15727-15734 ◽

Cited By ~ 77

Author(s):

Qing Lu ◽

Amanda E. Hutchins ◽

Colleen M. Doyle ◽

James R. Lundblad ◽

Roland P. S. Kwok

Keyword(s):

Binding Protein ◽

Creb Binding Protein ◽

Element Binding Protein ◽

Responsive Element ◽

Camp Responsive Element Binding

Download Full-text

PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2015-02-626127 ◽

2015 ◽

Vol 125 (23) ◽

pp. 3609-3617 ◽

Cited By ~ 46

Author(s):

Jinjun Dang ◽

Lei Wei ◽

Jeroen de Ridder ◽

Xiaoping Su ◽

Alistair G. Rust ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tumor Suppressor ◽

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Genetic Alteration ◽

Human Leukemia ◽

Key Points ◽

Leukemia Development ◽

Common Target ◽

Mouse Mutagenesis

Key Points Heterozygous alterations of Pax5, the most common target of genetic alteration in ALL, promote ALL in mouse mutagenesis models. Leukemia development is accompanied by the acquisition of genetic alterations commonly observed in human leukemia.

Download Full-text

MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1621425114 ◽

2017 ◽

Vol 114 (8) ◽

pp. 2072-2077 ◽

Cited By ~ 25

Author(s):

Ding-Yu Lee ◽

Ting-Er Lin ◽

Chih-I Lee ◽

Jing Zhou ◽

Yi-Hsuan Huang ◽

...

Keyword(s):

Shear Stress ◽

Histone Deacetylases ◽

Inflammatory Responses ◽

Nuclear Accumulation ◽

Hemodynamic Forces ◽

Endothelial Response ◽

Vascular Physiology ◽

Responsive Element ◽

Retinoid Acid

Histone deacetylases (HDACs) and microRNAs (miRs) have emerged as two important epigenetic factors in the regulation of vascular physiology. This study aimed to elucidate the relationship between HDACs and miRs in the hemodynamic modulation of endothelial cell (EC) dysfunction. We found that miR-10a has the lowest expression among all examined shear-responsive miRs in ECs under oscillatory shear stress (OS), and a relatively high expression under pulsatile shear stress (PS). PS and OS alter EC miR-10a expression to regulate the expression of its direct target GATA6 and downstream vascular cell adhesion molecule (VCAM)-1. PS induces the expression, nuclear accumulation, and association of retinoid acid receptor-α (RARα) and retinoid X receptor-α (RXRα). RARα and RXRα serve as a “director” and an “enhancer,” respectively, to enhance RARα binding to RA-responsive element (RARE) and hence miR-10a expression, thus down-regulating GATA6/VCAM-1 signaling in ECs. In contrast, OS induces associations of “repressors” HDAC-3/5/7 with RARα to inhibit the RARα-directed miR-10a signaling. The flow-mediated miR-10a expression is regulated by Krüppel-like factor 2 through modulation in RARα–RARE binding, with the consequent regulation in GATA6/VCAM-1 in ECs. These results are confirmed in vivo by en face staining on the aortic arch vs. the straight thoracic aorta of rats. Our findings identify a mechanism by which HDACs and RXRα modulate the hormone receptor RARα to switch miR-10a expression and hence the proinflammatory vs. anti-inflammatory responses of vascular endothelium under different hemodynamic forces.

Download Full-text