Regulation of Gene Expression by the Hypoxia-Inducible Factors

Fedele, Anthony O.; Whitelaw, Murray L.; Peet, Daniel J.

doi:10.1124/mi.2.4.229

Cited by 75 publications

(66 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, articular cartilage exists naturally in a low oxygen environment. Hypoxia inducible factor (HIF) mediates transcription factors to allow chondrocytes to adapt to low oxygen tension [120]. Hypoxia has been shown to increase the synthesis of ECM proteins in vitro in both chondrocytes as well as hypoxia-induced chondrogenic differentiation of MSCs [67,121,122].…”

Section: Oxygen Tensionmentioning

confidence: 99%

Bioengineering of Articular Cartilage: Past, Present and Future

Felimban

Moulton

et al. 2013

Regen. Med.

View full text Add to dashboard Cite

The treatment of cartilage defects poses a clinical challenge owing to the lack of intrinsic regenerative capacity of cartilage. The use of tissue engineering techniques to bioengineer articular cartilage is promising and may hold the key to the successful regeneration of cartilage tissue. Natural and synthetic biomaterials have been used to recreate the microarchitecture of articular cartilage through multilayered biomimetic scaffolds. Acellular scaffolds preserve the microarchitecture of articular cartilage through a process of decellularization of biological tissue. Although promising, this technique often results in poor biomechanical strength of the graft. However, biomechanical strength could be improved if biomaterials could be incorporated back into the decellularized tissue to overcome this limitation.

show abstract

Section: Oxygen Tensionmentioning

confidence: 99%

Bioengineering of Articular Cartilage: Past, Present and Future

Felimban

Moulton

et al. 2013

Regen. Med.

View full text Add to dashboard Cite

show abstract

“…b subunit (also called ARNT) (16)(17)(18). During periods of normoxia, cellular HIF-a protein subunits are controlled by ubiquitin-targeted degradation, mediated through the hydroxylation of key proline residues.…”

Section: Clinical Relevancementioning

confidence: 99%

Hypoxia Up-Regulates Expression of Hemoglobin in Alveolar Epithelial Cells

Grek

Newton²,

Spyropoulos³

et al. 2011

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Alveolar epithelial cells are directly exposed to acute and chronic fluctuations in alveolar oxygen tension. Previously, we found that the oxygen-binding protein hemoglobin is expressed in alveolar Type II cells (ATII). Here, we report that ATII cells also express a number of highly specific transcription factors and other genes normally associated with hemoglobin biosynthesis in erythroid precursors. Because hypoxia-inducible factors (HIFs) were shown to play a role in hypoxia-induced changes in ATII homeostasis, we hypothesized that the hypoxia-induced increase in intracellular HIF exerts a concomitant effect on ATII hemoglobin expression. Treatment of cells from the ATII-like immortalized mouse lung epithelial cell line-15 (MLE-15) with hypoxia for 20 hours resulted in dramatic increases in cellular levels of HIF-2a protein and parallel significant increases in hemoglobin messenger RNA (mRNA) and protein expression, as compared with that of control cells cultured in normoxia. Significant increases in the mRNA of globin-associated transcription factors were also observed, and RNA interference (RNAi) experiments demonstrated that the expression of hemoglobin is at least partially dependent on the cellular levels of globin-associated transcription factor isoform 1 (GATA-1). Conversely, levels of prosurfactant proteins B and C significantly decreased in the same cells after exposure to hypoxia. The treatment of MLE-15 cells cultured in normoxia with prolyl 4-hydroxylase inhibitors, which mimic the effects of hypoxia, resulted in increases of hemoglobin and decreases of surfactant proteins. Taken together, these results suggest a relationship between hypoxia, HIFs, and the expression of hemoglobin, and imply that hemoglobin may be involved in the oxygen-sensing pathway in alveolar epithelial cells.Keywords: hemoglobin; alveolar epithelial cells; hypoxia; hypoxiainducible factor Pulmonary hypoxia occurs under both physiologic and pathologic conditions. In fact, a hypoxic environment is necessary for proper embryonic lung development, by promoting the formation of microvasculature and epithelial branching morphogenesis (the average fetal blood O 2 fraction is z2-5%) (1-3). However, postnatal decreases in alveolar oxygen tension as a result of pulmonary disease disrupt alveolar homeostasis. High-altitude ascent, pathologic conditions resulting in inadequate respiration, pulmonary edema after acute lung injury, or congestive heart failure may all result in decreased oxygen tension. Alveolar Type II (ATII) cells represent approximately two thirds of epithelial cell numbers, and are of special clinical interest because of their role in the production, secretion, and recycling of pulmonary surfactant (4). In addition, ATII cells differentiate into Type I (ATI ) cells upon epithelial injury, and also act to clear fluid from the alveolar space. Although numerous studies evaluated the effects of hypoxia on the pulmonary endothelium, few sought to identify hypoxia-regulated genes in alveolar epithelial cells.Our previous stu...

show abstract

“…In the presence of oxygen, activity of HIF-1␣ is also regulated by hydroxylation of asparagine-803 within the C-terminal transactivation domain (15,28,38,39). Under hypoxic conditions, these modifications of HIF-1␣ do not occur, leading to accumulation of the protein and increased ability to recruit coactivators (3,15,28,39,58). These enzymatic modifications can also be inhibited by iron chelation and cobalt ions (28).…”

mentioning

confidence: 99%

“…The hydroxylated HIF-1␣ binds to the von Hippel-Lindau tumor suppressor protein, which leads to polyubiquination and degradation via the proteasome (10,36,46,51). In the presence of oxygen, activity of HIF-1␣ is also regulated by hydroxylation of asparagine-803 within the C-terminal transactivation domain (15,28,38,39). Under hypoxic conditions, these modifications of HIF-1␣ do not occur, leading to accumulation of the protein and increased ability to recruit coactivators (3,15,28,39,58).…”

mentioning

confidence: 99%

Genetic Organization and Hypoxic Activation of the Kaposi's Sarcoma-Associated Herpesvirus ORF34-37 Gene Cluster

Haque

Wang

Davis

et al. 2006

J Virol

View full text Add to dashboard Cite

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). We previously reported that hypoxia activates KSHV lytic replication and that the promoter for open reading frame 34 (ORF34) contains a functional hypoxia-responsive element (HRE). ORF34 is part of a cluster of lytic genes (ORF34-37) that includes ORF36, a phosphotransferase, and ORF37, a shutoff exonuclease. Rapid amplification of cDNA ends analysis revealed that they share a common polyadenylation signal but have two start sites. Two transcripts were identified, one 3.4 kb encoding ORF35-37, and the other 4.2 kb encoding ORF34 and also having coding potential for ORF35-37. Exposure of PEL cell lines to hypoxia induced messages of lengths consistent with those of these transcripts. Reporter assays with Hep3B cells showed activation of both transcripts by hypoxia. The ORF34-37 promoter region has six consensus HREs. Sequential deletion, site-directed mutagenesis experiments, and Northern blot analysis of RNA produced by constructs indicated that the second HRE (HRE-2) plays a critical role in the hypoxic activation of both RNA transcripts. The ORF35-37 transcript was upregulated by cotransfected hypoxia-inducible factor (HIF). Electrophoretic mobility shift assays demonstrated that HRE-2 and ancillary sequences bind and compete for HIF with hypoxic Hep3B nuclear extract. The activation of this gene cluster by hypoxia may have implications for the pathogenesis of PEL and KS. Moreover, the activation of ORF36 by hypoxia might be exploited to develop targeted therapy for PEL, which arises in a hypoxic environment (pleural effusions).

show abstract

Regulation of Gene Expression by the Hypoxia-Inducible Factors

Cited by 75 publications

References 0 publications

Bioengineering of Articular Cartilage: Past, Present and Future

Bioengineering of Articular Cartilage: Past, Present and Future

Hypoxia Up-Regulates Expression of Hemoglobin in Alveolar Epithelial Cells

Genetic Organization and Hypoxic Activation of the Kaposi's Sarcoma-Associated Herpesvirus ORF34-37 Gene Cluster

Contact Info

Product

Resources

About