aHIF: a Natural Antisense Transcript Overexpressed in Human Renal Cancer and During Hypoxia

Thrash-Bingham, Catherine; Tartof, Kenneth D.

doi:10.1093/jnci/91.2.143

Cited by 204 publications

(145 citation statements)

References 67 publications

Supporting

Mentioning

141

Contrasting

Order By: Relevance

“…Analysis of the HIF␣ mRNAs did not show any variation in acute or chronic hypoxia, ruling out the putative contribution of the antisense HIF1␣ previously described (16). However, we show that the bona fide hydroxylation-ubiquitination-proteasome pathway mediates HIF␣ protein decrease as recently reported by Stiehl et al (13).…”

Section: Discussionsupporting

confidence: 81%

PHDs overactivation during chronic hypoxia “desensitizes” HIFα and protects cells from necrosis

Ginouvès

Ilc

Macías³

et al. 2008

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

223

186

View full text Add to dashboard Cite

Cell adaptation to changes in oxygen (O2) availability is controlled by two subfamilies of O2-dependent enzymes: the hypoxia inducible factor (HIF)-prolyl and asparaginyl hydroxylases [prolyl hydroxylases domain (PHDs) and factor inhibiting HIF (FIH)]. These oxygen sensors regulate the activity of the HIF, a transcriptional complex central in O 2 homeostasis. In well oxygenated cells, PHDs hydroxylate the HIF␣ subunits, thereby targeting them for proteasomal degradation. In contrast, acute hypoxia inhibits PHDs, leading to HIF␣ stabilisation. However, here we show that chronic hypoxia induces HIF1/2␣''desensitization'' in cellulo and in mice. At the basis of this general adaptative mechanism, we demonstrate that chronic hypoxia not only increases the pool of PHDs but also overactivates the three PHD isoforms. This overactivation appears to be mediated by an increase in intracellular O 2 availability consequent to the inhibition of mitochondrial respiration. By using in cellulo and in vivo siRNA, we found that the PHDs are the key enzymes triggering HIF␣ desensitization, a feedback mechanism required to protect cells against necrotic cell death and thus to adapt them across a chronic hypoxia. Hence, PHDs serve as dual enzymes, for which inactivation and later overactivation is necessary for cell survival in acute or chronic hypoxia, respectively.cell survival ͉ oxygen sensing T he transcriptional complex hypoxia inducible factor (HIF) plays a central role in the maintenance of oxygen (O 2 ) homeostasis, which is essential for cell survival (1). HIF is tightly regulated in an O 2 -dependent manner by hydroxylation of one of the three HIF␣ subunits (HIF1␣, HIF2␣, and HIF3␣) (2, 3). In well oxygenated cells (normoxia), the hydroxylation of two proline residues (P 402 and P 564 in human HIF1␣) by the HIF-prolyl hydroxylases [prolyl hydroxylases domains (PHDs)] allows the specific recognition and polyubiquitination by the von Hippel-Lindau protein (pVHL) E3-ligase complex, leading to proteasomal degradation (4). Moreover, the hydroxylation of an asparagine residue (N 803 in human HIF1␣) by the factor inhibiting HIF (FIH) prevents binding of the coactivator p300/CBP and hence blocks HIF transcriptional activity (5). In contrast, restricted O 2 availability, by relaxing HIF␣ hydroxylation, results in HIF␣ stabilization and activation of the HIF transcriptional complex. Like FIH, the PHDs belong to the super family of iron-and 2-oxoglutarate-dependent dioxygenases, which, by using O 2 as a cosubstrate, provide the molecular basis for their O 2 -sensing function (6). In mammalian cells, three PHDs isoforms have been identified (PHD1, PHD2, and PHD3) and shown to hydroxylate HIF1␣ in cellulo depending on their relative abundance (7). Nevertheless, we report that PHD2 has a dominant role, as it is the rate-limiting enzyme that sets the low steady-state level of HIF1␣ in normoxia (8).In line with our previous work, we sought to look for HIF␣ regulation during long-term hypoxia. Contrary to acute hypoxia, we observed that chr...

show abstract

Section: Discussionsupporting

confidence: 81%

PHDs overactivation during chronic hypoxia “desensitizes” HIFα and protects cells from necrosis

Ginouvès

Ilc

Macías³

et al. 2008

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

223

186

View full text Add to dashboard Cite

show abstract

“…Besides by factors mentioned earlier, the expression of HIF1a is also regulated by aHIF, a naturally occurring antisense transcript RNA that forms a double-stranded RNA molecule with the antisense transcript of HIF1a (Thrash-Bingham & Tartof 1999, Uchida et al 2004. Naturally occurring antisense transcript expression can lead to the downregulation of the sense transcript by RNA interference (Yelin et al 2003, Chen et al 2004.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia initially induces increased expression of HIF-1a, but during sustained hypoxia, the amount of HIF-1a mRNA is reduced (Wenger et al 1998). Instead, there is considerable overexpression of the HIF-1a natural antisense transcript (aHIF), which encodes the antisense template of the 3 0 -untranslated region of HIF-1a mRNA (Thrash-Bingham & Tartof 1999). This represents a negative feedback loop, in which aHIF inhibits the translation of HIF-1a mRNA after chronic hypoxia (Uchida et al 2004).…”

Section: Introductionmentioning

confidence: 99%

“…This situation is reversed during later stages of hypoxia, when HIF-1a translation is inhibited by aHIF (Uchida et al 2004), resulting in the loss of p53 followed by deregulated cell proliferation. Thus, aHIF expression also allows tumor cells to survive hypoxia without inducing the tumor suppressor p53 (Thrash-Bingham & Tartof 1999). Theoretically, aHIF expression is not mainly a phenotypical sign of chronic hypoxia but also in itself mechanistically associated with more aggressive tumor behavior and increased metastatic potential (Cayre et al 2003).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Overexpression of the natural antisense hypoxia-inducible factor-1 transcript is associated with malignant pheochromocytoma/paraganglioma

Span

Rao²,

Ophuis³

et al. 2011

Endocrine Related Cancer

View full text Add to dashboard Cite

Paragangliomas (PGLs) have widely different metastastic potentials. Two different types of PGLs can be defined by expression profiling. Cluster 1 PGLs exhibit VHL and/or succinate dehydrogenase (SDH) mutations and a pseudohypoxic phenotype. RET and neurofibromatosis type 1 (NF1) mutations occur in cluster 2 tumors characterized by deregulation of the RAS/RAF/MAP kinase signaling cascade. Sporadic PGLs can exhibit either profile. During sustained hypoxia, a natural antisense transcript of hypoxia-inducible factor 1 (aHIF) is expressed. The role of aHIF in the metastatic potential of PGL has not yet been investigated. The aim was to test the hypothesis that genotype-specific overexpression of aHIF is associated with an increased metastatic potential. Tumor samples were collected from 87 patients with PGL. Quantitative PCR was performed for aHIF, vascular endothelial growth factor (VEGF), aquaporin 3, cytochrome b561, p57Kip2, slit homolog 3, and SDHC. Expression was related to mutation status, benign versus malignant tumors, and metastasis-free survival. We found that both aHIF and VEGF were overexpressed in cluster 1 PGLs and in metastatic tumors. In contrast, slit homolog 3, p57Kip2, cytochrome b561, and SDHC showed overexpression in non-metastatic tumors, whereas no such difference was observed for aquaporin 3. Patients with higher expression levels of aHIF and VEGF had a significantly decreased metastasisfree survival. Higher expression levels of SDHC are correlated with an increased metastasis-free survival. In conclusion, we not only demonstrate a higher expression of VEGF in cluster 1 PGL, fitting a profile of pseudohypoxia and angiogenesis, but also of aHIF. Moreover, overexpression of aHIF and VEGF marks a higher metastatic potential in PGL.

show abstract

“…However, prolonged exposure to hypoxia in tissue culture cells and in the whole organism leads to decreased HIF-1a MRNA (Wenger et al, , 1998. Recently an endogenous occurring HIF-1a antisense transcript (termed aHIF) arising from the 3'UTR of HIF-1a mRNA was identi®ed in nonpapillary renal clear cell carcinoma (Trash-Bingham and Tartof, 1999). The aHIF transcript is not overexpressed in papillary renal carcinomas and only nonpapillary tumors are characterized by dysfunction of the VHL gene .…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of hypoxia-inducible factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function

et al. 2000

View full text Add to dashboard Cite

Hypoxia induces transcription of a range of physiologically important genes including erythropoietin and vascular endothelial growth factor. The transcriptional activation is mediated by the hypoxia-inducible factor-1 (HIF-1), a heterodimeric member of the basic helix ± loop ± helix PAS family, composed of a and b subunits. HIF-1a shares 48 per cent identity with the recently identi®ed HIF-2a protein that is also stimulated by hypoxia. In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von HippelLindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2a mRNA in stromal cells of the tumors. Mutations of the VHL tumor suppressor gene are associated with a variety of tumors such as renal clear cell carcinomas (RCC). In this study, we analysed the expression of the hypoxiainducible factors HIF-1a and HIF-2a in a range of VHL wildtype and VHL de®cient RCC cell lines. In the presence of functional VHL protein, HIF-1a mRNA levels are elevated, whereas HIF-2a mRNA expression is increased only in cells lacking a functional VHL gene product. On the protein levels, however, in VHL de®cient cell lines, both HIF-a subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1a and HIF-2a proteins under normoxic conditions. Moreover, immunohistochemical analyses of RCCs and hemangioblastomas demonstrate up-regulation of HIF-1a and HIF-2a in the tumor cells. The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1a and HIF-2a proteins. Oncogene (2000) 19, 5435 ± 5443.

show abstract

aHIF: a Natural Antisense Transcript Overexpressed in Human Renal Cancer and During Hypoxia

Cited by 204 publications

References 67 publications

PHDs overactivation during chronic hypoxia “desensitizes” HIFα and protects cells from necrosis

PHDs overactivation during chronic hypoxia “desensitizes” HIFα and protects cells from necrosis

Overexpression of the natural antisense hypoxia-inducible factor-1 transcript is associated with malignant pheochromocytoma/paraganglioma

Up-regulation of hypoxia-inducible factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function

Contact Info

Product

Resources

About