The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsFoxler, Daniel E
Bridge, Katherine S
Webb, Thomas M
Wong, Sybil C K
Petursdottir, Thorgunnur Eyfjord
Ratcliffe, Peter J
Longmore, Gregory D
Sharp, Tyson V
MetadataShow full item record
CitationNat. Cell Biol. 2012, 14(2):201-8
AbstractThere are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1α, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1α ubiquitylation and degradation. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1α or as a multiprotein complex. Here we show that the tumour suppressor protein LIMD1 (LIM domain-containing protein) acts as a molecular scaffold, simultaneously binding the PHDs and VHL, thereby assembling a PHD-LIMD1-VHL protein complex and creating an enzymatic niche that enables efficient degradation of HIF-1α. Depletion of endogenous LIMD1 increases HIF-1α levels and transcriptional activity in both normoxia and hypoxia. Conversely, LIMD1 expression downregulates HIF-1 transcriptional activity in a manner depending on PHD and 26S proteasome activities. LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators.
RightsArchived with thanks to Nature cell biology
- Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition.
- Authors: Chintala S, Najrana T, Toth K, Cao S, Durrani FA, Pili R, Rustum YM
- Issue date: 2012 Jul 17
- Deregulation of LIMD1-VHL-HIF-1α-VEGF pathway is associated with different stages of cervical cancer.
- Authors: Chakraborty C, Mitra S, Roychowdhury A, Samadder S, Dutta S, Roy A, Das P, Mandal RK, Sharp TV, Roychoudhury S, Panda CK
- Issue date: 2018 May 31
- RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect.
- Authors: Zhang CS, Liu Q, Li M, Lin SY, Peng Y, Wu D, Li TY, Fu Q, Jia W, Wang X, Ma T, Zong Y, Cui J, Pu C, Lian G, Guo H, Ye Z, Lin SC
- Issue date: 2015 Sep
- Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha.
- Authors: André H, Pereira TS
- Issue date: 2008 Oct 24
- OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha.
- Authors: Baek JH, Mahon PC, Oh J, Kelly B, Krishnamachary B, Pearson M, Chan DA, Giaccia AJ, Semenza GL
- Issue date: 2005 Feb 18