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Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells
Author(s) -
Balasenthil Seetharaman,
Barnes Christopher J.,
Rayala Suresh K.,
Kumar Rakesh
Publication year - 2004
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.04.071
Subject(s) - cyclin d1 , estrogen receptor , transactivation , estrogen receptor alpha , downregulation and upregulation , cancer research , estrogen receptor beta , cyclin d , biology , cyclin , microbiology and biotechnology , chemistry , cell cycle , gene expression , gene , cancer , breast cancer , biochemistry , genetics
Recent studies have shown that p21‐activated kinase 1 (Pak1) phosphorylates estrogen receptor‐α (ERα) at Ser 305 and also promotes its transactivation function. Here, we sought to investigate whether substitution of serine 305 in ER with glutamic acid (ERα‐S305E), which mimics the phosphorylation state, would influence the status of ER‐target genes. To explore this possibility, we generated clones overexpressing ERα‐S305E in ER‐negative MDA‐MB‐231 cells and analyzed the status of ER‐regulated genes using a gene array. Results indicated that the expression of ERα‐S305E is sufficient to upregulate the expression of a few but not all ER‐regulated genes, i.e., cyclin D1 and zinc finger protein 147 (estrogen‐responsive finger protein), while there was no significant change in the expression of remaining genes on the array. In addition, we found an increased expression as well as nuclear accumulation of cyclin D1 protein in MDA‐MB‐231 cells expressing ERα‐S305E as compared to the level of cyclin D1 in MDA‐MB‐231 cells expressing WT‐ERα or pcDNA. Furthermore, ERα‐S305E, but not mutation of ERα‐S305 to alanine, enhanced the cyclin D1 promoter activity. These findings suggest that ERα activation at S305 is sufficient to upregulate the expression of cyclin D1, an ER‐regulated gene that is implicated in the progression of breast cancer. Phosphorylation of ERα by Pak1 or its upstream regulators could upregulate the expression of a subset of ER‐target genes in a ligand‐independent manner and hence, might contribute toward the development of hormone independence in breast cancer cells.