Hypoxia-Induced Energy Stress Regulates mRNA Translation and Cell Growth

Liu, Liping; Cash, Timothy P.; Jones, Russell G.; Keith, Brian; Thompson, Craig B.; Simon, M. Celeste

doi:10.1016/j.molcel.2006.01.010

Cited by 551 publications

(518 citation statements)

References 37 publications

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“…Analyses over a time course of severe hypoxia (<0.01% oxygen) or CoCl 2 treatment show that neither loss of functional HIF-1α nor HIF-1β inhibited hypoxia-induced repression of total RNA synthesis. A HIF-1-independent mechanism of widespread transcription repression may facilitate energy conservation during hypoxia, an ATP-limiting stress [11], and allow hypoxic tumor cells to channel their energy toward activation of genes that promote survival.…”

Section: Hypoxia Induces Global Repression Of Transcription Independementioning

confidence: 99%

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

Johnson¹,

Denko²,

Barton³

2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

236

207

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Tumor cells respond to the harsh hypoxic microenvironment, in part, by transcriptional regulation of specific target genes. We found that hypoxia-mediated activation of selected genes occurs amidst widespread repression of transcription that is neither cell type-specific nor HIF-1-dependent. Despite overall repression, hypoxia induces a pool of histone modifications typically associated with transcriptional activation or repression. Chromatin immunoprecipitation analyses showed that this global mixture of hypoxia-modified histones is sorted in a gene-specific manner to correlate with transcriptional response to hypoxia. Exceptions to this were unexpected increases in H3K4me3 levels, typically associated with transcriptional activation, and decreased H3K27me3 levels, generally a marker of transcriptional silencing, at core promoters of both hypoxia-activated andrepressed genes. These data suggest that a novel signature of chromatin modifications is induced under hypoxic stress, which may play a role in gene regulatory switches active in proliferating tumor cells undergoing cycles of hypoxia and reoxygenation.

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Section: Hypoxia Induces Global Repression Of Transcription Independementioning

confidence: 99%

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

Johnson¹,

Denko²,

Barton³

2008

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

236

207

View full text Add to dashboard Cite

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“…Hypoxia in mammals limits protein synthesis by at least two distinct mechanisms regulated in a temporally biphasic manner (Koritzinsky et al, 2006;Liu et al, 2006). One involves the eIF2a kinase PERK (PKR-like ER kinase) phosphorylating eIF2a on Ser51 (Koumenis et al, 2002).…”

Section: Hypoxiamentioning

confidence: 99%

“…Chronic hypoxia leads to the accumulation of hypophosphorylated 4E-BP and hence increased binding to eIF4E (Tinton and Buc-Calderon, 1999;Connolly et al, 2006). mTOR activity is downregulated under acute low oxygen regimes in an HIF-1-and ATP level-independent manner, as shown by a reduction in phospho-S6K/S6 and phospho-4E-BP phosphorylation (Arsham et al, 2003;Brugarolas et al, 2004;Liu et al, 2006). Non-transformed cells generally reduce translation rates to a much higher extent than fully transformed cancer cell lines, arguing that the latter ones uncouple the growth-inhibitory effects of hypoxia from translation (Connolly et al, 2006).…”

Section: Hypoxiamentioning

confidence: 99%

“…Accordingly, lack of TSC function in low-oxygen conditions results in higher translation rates, increased proliferation and/or increased survival (Brugarolas et al, 2004;Kaper et al, 2006;Liu et al, 2006). The hypoxia-inducible RTP801/REDD1/2 proteins and their Drosophila homologs Scylla and Charybdis have been identified as negative growth modulators upstream of TSC1/2.…”

Section: Hypoxiamentioning

confidence: 99%

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Stress and mTORture signaling

2006

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“…Hypoxia triggers several additional signaling mechanisms, many of which interface with HIF-dependent signaling. Under hypoxia, the reduction of energy production has a major negative impact on the translational rate of proteins, as hypoxia and HIF-1α inhibit mTOR signaling, a critical signaling pathway involved in the induction of cell growth and protein synthesis [2].…”

Section: Hypoxia Signaling In the Lungmentioning

confidence: 99%

Hypoxia and chronic lung disease

et al. 2007

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The lung is both the conduit for oxygen uptake and is also affected by hypoxia and hypoxia signaling. Decreased ventilatory drive, airway obstructive processes, intra-alveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/arterial pO 2 gradient. These processes result in decreased blood and tissue oxygenation. This review addresses the relationship of hypoxia with lung development and with lung diseases. We particularly focus on molecular mechanisms underlying hypoxia-driven physiological and pathophysiological lung processes, specifically in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease.Keywords Hypoxia . Lung . Pathology . HIF Air, containing oxygen at approximately 21% partial pressure at sea level (140-150 mmHg), travels through up to 20 generations of airways by mass flow and then diffuses into the gas exchange units (alveoli) in the lung with a partial pressure of approximately 105-110 mmHg. The human lung contains approximately 480 million alveoli, which represent 64% of total lung structure. These alveoli are elegantly packed in only 1.3-2.6 L of total lung volume, providing a surface area of 120-150 m 2 , equivalent to the dimensions of a "tennis court" dedicated for gas exchange. Although the molecular determinants of lung size are not known, oxygen diffusion constant and gas exchange surface area are roughly proportional to body weight and oxygen consumption in different species [1]. Physical hyperactivity and exposure to a cold environment or high altitude lead to increased oxygen diffusion capacity, in proportion to enhanced oxygen consumption [1].Decreased ventilatory drive, airway obstructive processes, intraalveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/ arterial pO 2 gradient. This review addresses the contribution of hypoxia to lung diseases and the potential molecular mechanisms involved in hypoxia-driven physiological and pathophysiological lung processes (Fig. 1), particularly in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease. The fundamental concepts underlying hypoxia-induced gene expression and the molecular regulation of HIF(s) also apply to the lung, and they will be cited in relation to their demonstrated role in lung physiology or pathophysiology.

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Hypoxia-Induced Energy Stress Regulates mRNA Translation and Cell Growth

Cited by 551 publications

References 37 publications

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

Stress and mTORture signaling

Hypoxia and chronic lung disease

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