Expression of tumor-promoting Cyr61 is regulated by hTRA2-β1 and acidosis.

Hum Mol Genet 2011 Jun 29;20(12):2356-65. Epub 2011 Mar 29.

Gynaecological Hospital, Freiburg University Medical Center, Hugstetterstr. 55, D-79106 Freiburg, Germany.

The matricellular protein Cysteine rich 61 (Cyr61) displays a remarkable diversity of multiple cellular functions involved in significant physiologic and pathologic processes. Cyr61 is known as an important player in tumor progression, promoting neovascularization and metastasis. Our prior investigations elucidated an oxygen-dependent Cyr61 alternative splicing process characterized by retention of its intron 3, regulating its biological function in a hypoxia-driven on/off switch mechanism. In this work, we identified extracellular acidosis as a potent inducer for altered Cyr61 alternative splicing pattern regulating Cyr61 expression. Intriguingly, splicing factor hTRA2-beta1 displayed an opposite effect on Cyr61 expression. Nuclear hTRA2-beta1 protein expression was found markedly reduced under acidic conditions. In keeping with these conclusions, we show that hTRA2-beta1 can specifically bind a 'GAAG' motif in Cyr61 exon 3 RNA, that the splicing factor displays acidosis-dependent protein localization in cellular compartments, and shRNA-mediated hTRA2-beta1 knock-down triggers the same effects on Cyr61 alternative splicing like acidosis or hypoxia. Our findings strongly support the hypothesis of a specific regulation of Cyr61 expression by hTRA2-beta1.

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddr128DOI Listing
June 2011
13 Reads

Publication Analysis

Top Keywords

alternative splicing
12
cyr61 expression
12
cyr61 alternative
12
cyr61
10
splicing factor
8
htra2-beta1
5
expression
5
splicing
5
intriguingly splicing
4
htra2-beta1 protein
4
expression intriguingly
4
protein expression
4
regulating cyr61
4
nuclear htra2-beta1
4
expression nuclear
4
pattern regulating
4
opposite cyr61
4
htra2-beta1 displayed
4
factor htra2-beta1
4
displayed opposite
4

References

(Supplied by CrossRef)

Buratti et al.
Nucleic Acids Research 2006

Baralle et al.
EMBO Reports 2009

Bork et al.
FEBS Letters 1993

O'Brien et al.
Molecular and Cellular Biology 1990

Leask et al.
Journal of Cell Science 2006

Chen et al.
Journal of cellular biochemistry 2007

Lau et al.
Experimental cell research 1999

O'Kelly et al.
International journal of oncology 2008

Xie et al.
Clinical Cancer Research 2004

Bleau et al.
Frontiers in bioscience : a journal and virtual library 2005

2001

Similar Publications