von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination.
Anna V. Kuznetsova,Jaroslaw Meller,Phillip O. Schnell,James A. Nash,Monika L. Ignacak,Yolanda Sanchez,Joan W. Conaway,Ronald C. Conaway,Maria F. Czyzyk-Krzeska +8 more
TLDR
In this paper, the authors identified regions of Rpb1 and the adjacent subunit 6 of RNA polymerase II (Rpb6) that share sequence and structural similarity with the domain of hypoxia-inducible transcription factor 1α that binds von Hippel-Lindau tumor suppressor protein (pVHL).Abstract:
The transition from transcription initiation to elongation involves phosphorylation of the large subunit (Rpb1) of RNA polymerase II on the repetitive carboxyl-terminal domain. The elongating hyperphosphorylated Rpb1 is subject to ubiquitination, particularly in response to UV radiation and DNA-damaging agents. By using computer modeling, we identified regions of Rpb1 and the adjacent subunit 6 of RNA polymerase II (Rpb6) that share sequence and structural similarity with the domain of hypoxia-inducible transcription factor 1α (HIF-1α) that binds von Hippel–Lindau tumor suppressor protein (pVHL). pVHL confers substrate specificity to the E3 ligase complex, which ubiquitinates HIF-α and targets it for proteasomal degradation. In agreement with the computational model, we show biochemical evidence that pVHL specifically binds the hyperphosphorylated Rpb1 in a proline-hydroxylation-dependent manner, targeting it for ubiquitination. This interaction is regulated by UV radiation.read more
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Journal ArticleDOI
Regulation of angiogenesis by hypoxia: role of the HIF system.
TL;DR: The role of HIF in developmental, adaptive and neoplastic angiogenesis, and the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype are discussed.
Journal ArticleDOI
Oxygen sensing by HIF hydroxylases
TL;DR: The transcription factor HIF (hypoxia-inducible factor) has a central role in oxygen homeostasis in animals ranging from nematode worms to man and is regulated by an unprecedented signalling mechanism that involves post-translational hydroxylation.
Journal ArticleDOI
HIF prolyl‐hydroxylase 2 is the key oxygen sensor setting low steady‐state levels of HIF‐1α in normoxia
Edurne Berra,Emmanuel Benizri,Amandine Ginouvès,Véronique Volmat,Danièle Roux,Jacques Pouysségur +5 more
TL;DR: It is shown that specific ‘silencing’ of PHD2 with short interfering RNAs is sufficient to stabilize and activate HIF‐1α in normoxia in all the human cells investigated, concluding that, in vivo, PHDs have distinct assigned functions.
Journal ArticleDOI
The general transcription machinery and general cofactors.
Mary C. Thomas,Cheng Ming Chiang +1 more
TL;DR: These cofactors are capable of repressing basal transcription when activators are absent and stimulating transcription in the presence of activators, with emphasis on the events occurring after the chromatin has been remodeled but prior to the formation of the first phosphodiester bond.
Journal ArticleDOI
Role of VHL Gene Mutation in Human Cancer
William Y. Kim,William G. Kaelin +1 more
TL;DR: Preliminary data indicate that HIF plays a critical role in pVHL-defective tumor formation, raising the possibility that drugs directed against HIF or its downstream targets (such as vascular endothelial growth factor) might one day play a role in the treatment of hemangioblastoma and renal cell carcinoma.
References
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Journal ArticleDOI
Protein secondary structure prediction based on position-specific scoring matrices
TL;DR: A two-stage neural network has been used to predict protein secondary structure based on the position specific scoring matrices generated by PSI-BLAST and achieved an average Q3 score of between 76.5% to 78.3% depending on the precise definition of observed secondary structure used, which is the highest published score for any method to date.
Journal ArticleDOI
Targeting of HIF-alpha to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation
Panu Jaakkola,David R. Mole,Ya-Min Tian,Michael I. Wilson,Janine Gielbert,Simon J. Gaskell,Alex von Kriegsheim,Holger F. Hebestreit,Mridul Mukherji,Christopher J. Schofield,Patrick H. Maxwell,Christopher W. Pugh,Peter J. Ratcliffe +12 more
TL;DR: It is shown that the interaction between human pVHL and a specific domain of the HIF-1α subunit is regulated through hydroxylation of a proline residue by an enzyme the authors have termed Hif-α prolyl-hydroxylase (HIF-PH).
Journal ArticleDOI
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing
Mircea Ivan,Keiichi Kondo,Haifeng Yang,William Y. Kim,Jennifer Valiando,Michael Ohh,Adrian Salic,John M. Asara,William S. Lane,William G. Kaelin,William G. Kaelin +10 more
TL;DR: It is found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated, which may play a key role in mammalian oxygen sensing.
Journal ArticleDOI
C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.
Andrew C. R Epstein,Jonathan M. Gleadle,Luke A. McNeill,Kirsty S. Hewitson,J F O'Rourke,David R. Mole,Mridul Mukherji,Eric Metzen,Michael A Wilson,Anu Dhanda,Ya-Min Tian,Norma Masson,Donald L. Hamilton,Panu Jaakkola,Robert Barstead,Jonathan Hodgkin,Patrick H. Maxwell,Christopher W. Pugh,Christopher J. Schofield,Peter J. Ratcliffe +19 more
TL;DR: Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrors the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF.
Journal ArticleDOI
A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF
TL;DR: In cultured mammalian cells, inappropriate accumulation of HIF caused by forced expression of the HIF-1α subunit under normoxic conditions was attenuated by coexpression of HPH, indicating that HPH is an essential component of the pathway through which cells sense oxygen.
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C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.
Andrew C. R Epstein,Jonathan M. Gleadle,Luke A. McNeill,Kirsty S. Hewitson,J F O'Rourke,David R. Mole,Mridul Mukherji,Eric Metzen,Michael A Wilson,Anu Dhanda,Ya-Min Tian,Norma Masson,Donald L. Hamilton,Panu Jaakkola,Robert Barstead,Jonathan Hodgkin,Patrick H. Maxwell,Christopher W. Pugh,Christopher J. Schofield,Peter J. Ratcliffe +19 more