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TLX controls angiogenesis through interaction with the von Hippel-Lindau protein

Authors :
Zhao-jun Zeng
Erik Johansson
Amiko Hayashi
Pavithra L. Chavali
Nina Akrap
Takeshi Yoshida
Kimitoshi Kohno
Hiroto Izumi
Keiko Funa
Source :
Biology Open, Vol 1, Iss 6, Pp 527-535 (2012)
Publication Year :
2012
Publisher :
The Company of Biologists, 2012.

Abstract

Summary TLX is known as the orphan nuclear receptor indispensable for maintaining neural stem cells in adult neurogenesis. We report here that neuroblastoma cell lines express high levels of TLX, which further increase in hypoxia to enhance the angiogenic capacity of these cells. The proangiogenetic activity of TLX appears to be induced by its direct binding to the von Hippel-Lindau protein (pVHL), which stabilizes TLX. In turn, TLX competes with hydroxylated hypoxia-inducible factor (HIF-α) for binding to pVHL, which contributes to the stabilization of HIF-2α in neuroblastoma during normoxia. Upon hypoxia, TLX increases in the nucleus where it binds in close proximity of the HIF-response element on the VEGF-promoter chromatin, and, together with HIF-2α, recruits RNA polymerase II to induce VEGF expression. Conversely, depletion of TLX by shRNA decreases the expression of HIF-2α and VEGF as well as the growth-promoting and colony-forming capacity of the neuroblastoma cell lines IMR-32 and SH-SY5Y. On the contrary, silencing HIF-2α will slightly increase TLX, suggesting that TLX acts to maintain a hypoxic environment when HIF-2α is decreasing. Our results demonstrate TLX to play a key role in controlling angiogenesis by regulating HIF-2α. TLX and pVHL might counterbalance each other in important fate decisions such as self-renewal and differentiation, as well as angiogenesis and anti-angiogenesis.

Details

Language :
English
ISSN :
20466390
Volume :
1
Issue :
6
Database :
Directory of Open Access Journals
Journal :
Biology Open
Publication Type :
Academic Journal
Accession number :
edsdoj.9e1d07fdd7ad47bd9c8367ab22d413cb
Document Type :
article
Full Text :
https://doi.org/10.1242/bio.2012893