Phosphorylation by p38 mitogen-activated protein kinase promotes estrogen receptor α turnover and functional activity via the SCF(Skp2) proteasomal complex
Language: 
English
Abstract: 

The nuclear hormone receptor estrogen receptor α (ERα) mediates the actions of estrogens in target cells and is a master regulator of the gene expression and proliferative programs of breast cancer cells. The presence of ERα in breast cancer cells is crucial for the effectiveness of endocrine therapies, and its loss is a hallmark of endocrine-insensitive breast tumors. However, the molecular mechanisms underlying the regulation of the cellular levels of ERα are not fully understood. Our findings reveal a unique cellular pathway involving the p38 mitogen-activated protein kinase (p38MAPK)-mediated phosphorylation of ERα at Ser-294 that specifies its turnover by the SCF(Skp2) proteasome complex. Consistently, we observed an inverse relationship between ERα and Skp2 or active p38MAPK in breast cancer cell lines and human tumors. ERα regulation by Skp2 was cell cycle stage dependent and critical for promoting the mitogenic effects of estradiol via ERα. Interestingly, by the knockdown of Skp2 or the inhibition of p38MAPK, we restored functional ERα protein levels and the control of gene expression and proliferation by estrogen and antiestrogen in ERα-negative breast cancer cells. Our findings highlight a novel pathway with therapeutic potential for restoring ERα and the responsiveness to endocrine therapy in some endocrine-insensitive ERα-negative breast cancers.

Author(s): 
Bhatt, Shweta
Xiao, Zhen
Meng, Zhaojing
Katzenellenbogen, Benita S.
Item Type: 
Journal Article
Publication Title: 
Molecular and Cellular Biology
Journal Abbreviation: 
Mol. Cell. Biol.
Publication Date: 
May 2012
Publication Year: 
2012
Pages: 
1928-1943
Volume: 
32
Issue: 
10
ISSN: 
1098-5549
DOI: 
10.1128/MCB.06561-11
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 22431515 PMCID: PMC3347406

Turabian/Chicago Citation

Shweta Bhatt, Zhen Xiao, Zhaojing Meng and Benita S. Katzenellenbogen. May 2012. "Phosphorylation by p38 mitogen-activated protein kinase promotes estrogen receptor α turnover and functional activity via the SCF(Skp2) proteasomal complex." Molecular and Cellular Biology 32: 10: 1928-1943. 10.1128/MCB.06561-11.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1128/MCB.06561-11 | issn = 1098-5549 | volume = 32 | pages = 1928-1943 | last = Bhatt | first = Shweta | coauthors = Xiao, Zhen, Meng, Zhaojing, Katzenellenbogen, Benita S. | title = Phosphorylation by p38 mitogen-activated protein kinase promotes estrogen receptor α turnover and functional activity via the SCF(Skp2) proteasomal complex | journal = Molecular and Cellular Biology | date = May 2012 | pmid = | pmc = }} </ref>