Regulation of Transcription and Translation by Hypoxia

Liu, Liping; Simon, M. Celeste

doi:10.4161/cbt.3.6.1010

Cited by 172 publications

(124 citation statements)

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“…MYC displayed a distinct p53-dependent repression in wild-type HCT116 cells that was distinct from the generic decrease that occurs during hypoxia (51). This phenomenon may require cooperation with promoter elements that facilitate the recruitment of corepressor complexes (83).…”

Section: Discussionmentioning

confidence: 87%

Functional Analysis of p53 Binding under Differential Stresses

Krieg

Hammond

Giaccia

2006

Molecular and Cellular Biology

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Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (>2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (>2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (>2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.The tumor microenvironment is a major factor influencing tumor growth, metastatic potential, and response to chemotherapeutic drugs and radiation therapy (7). The hypoxia-inducible factor (HIF) family of transcription factors regulates the expression of key enzymes in anaerobic glycolysis and proangiogenic factors (i.e., vascular endothelial growth factor), aiding cells in adapting to a low-oxygen environment (15). Thus, a tumor adapts to hypoxia first by sustaining itself via anaerobic metabolism and then by stimulating angiogenesis to acquire more nutrients and oxygen. However, the resulting vasculature tends to have aberrant structures with irregular blood flow and leaky walls, paradoxically creating regions of transient hypoxia and reoxygenation (76). Reoxygenation after hypoxia causes DNA damage, exacerbating genomic instability (25). The porous structure of the tumor vasculature may also provide an escape route for metastasizing cells. Repeated cycles of hypoxia, vascular formation, and reoxygenation select for cells that are more likely to survive in a restrictive environment. The consequences of this process are cancer cells that are more aggressive, more likely to metastasize, and more likely to be resistant to radiation and chemotherapy. Intimately tied to this process is the selection for cells that have lost the expression of functional p53 (19).A variety of cellular stresses, including DNA damage, oncogenic transformation, and hypoxia, stabilize the p53 protein by activating a host of stress-inducible kinases that phosphorylate p53 and MDM2, resulting in increased levels of p53 (17). Stabilized ...

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Section: Discussionmentioning

confidence: 87%

Functional Analysis of p53 Binding under Differential Stresses

Krieg

Hammond

Giaccia

2006

Molecular and Cellular Biology

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“…9,19 For example, regulation of expression of enzymes of the glycolytic pathway is a unique HIF-1α function, whereas control of erythropoiesis in vivo appears to be specific to HIF-2α; last, modulation of angiogenesis is a common function of both HIF-1α and HIF-2α. 19 Interestingly, expression of either HIF-1α or HIF-2α can be controlled by growth factors in a hypoxiaindependent manner.…”

Section: 4mentioning

confidence: 99%

“…HIF-1 6-10 consists of two basic helix-loop-helix proteins of the PER-ARNT-SIM subfamily, HIF-1α and HIF-1β, [9][10][11] which are ubiquitously expressed. 12 HIF-1α is activated when oxygen levels drop to <5%, which is detected by a class of 2-oxoglutarate-dependent and Fe 2+ -dependent prolyl hydroxylases (Figure 1).…”

Section: 4mentioning

confidence: 99%

Hypoxia-driven pathways in bone development, regeneration and disease

2012

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Adaptation to hypoxia is a critical cellular event both in pathological settings, such as cancer and ischemia, and in normal development and differentiation. Oxygen is thought to be not only an indispensable metabolic substrate for a variety of in vivo enzymatic reactions including mitochondrial respiration, but also a key regulatory signal in tissue development and homeostasis by controlling a specific genetic program. Hypoxiainducible transcription factors (HIFs) HIF-1 and HIF-2 are central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. Genetically altered mice have identified important roles for HIF-1 and HIF-2 as well as vascular endothelial growth factor-A (VEGF)-a potent angiogenic factor and a downstream target of the HIF pathway-in the regulation of skeletal development, bone homeostasis and haematopoiesis. In this Review, we summarize the current knowledge of HIF signalling in cartilage, bone and haematopoiesis, and pay particular attention to the complex relationship between HIF and VEGF in these tissues based on data collected in animal models. The study of these models expands our understanding of the cell autonomous, paracrine and autocrine effects that mediate the homeostatic responses downstream of HIFs and VEGF. This knowledge can also be relevant for diseases like cancer and ischemia.

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“…These observations raise the question of a more complex function and regulation of HIF1␣ in mammalian systems. Although much is known about the transcriptional and post-translational regulation of HIF1␣ (32,33), there are few reports that HIF1␣ can be degraded under conditions of hypoxia by the 26 S proteasome (30,34,35). Ravi et al (30) has suggested that p53 acts as a molecular chaperone that facilitates recruitment of HIF1␣ for ubiquitination by MDM2 under hypoxic conditions in a proteasome-dependent manner.…”

mentioning

confidence: 99%

MDM2 Regulates Hypoxic Hypoxia-inducible Factor 1α Stability in an E3 Ligase, Proteasome, and PTEN-Phosphatidylinositol 3-Kinase-AKT-dependent Manner

Joshi

Singh

Durden

2014

Journal of Biological Chemistry

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Background: HIF1␣ is degraded under normoxic conditions by VHL. Degradation under hypoxia is poorly understood. Results: HIF1␣ is degraded under hypoxia via 26 S proteasome; MDM2/E3 ligase, under the control of PI3K, mediates the hypoxic degradation of HIF1␣ in glioma systems. Conclusion: MDM2 action on HIF1␣ under hypoxia is controlled by PI3K signaling. Significance: Results reveal a mechanism controlling hypoxic HIF1␣ degradation.

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Regulation of Transcription and Translation by Hypoxia

Cited by 172 publications

References 53 publications

Functional Analysis of p53 Binding under Differential Stresses

Functional Analysis of p53 Binding under Differential Stresses

Hypoxia-driven pathways in bone development, regeneration and disease

MDM2 Regulates Hypoxic Hypoxia-inducible Factor 1α Stability in an E3 Ligase, Proteasome, and PTEN-Phosphatidylinositol 3-Kinase-AKT-dependent Manner

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