TY - JOUR
T1 - Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells
AU - Balasenthil, Seetharaman
AU - Barnes, Christopher J.
AU - Rayala, Suresh K.
AU - Kumar, Rakesh
N1 - Funding Information:
We thank Mahitosh Mandal for the initial characterization of stable clones. This work was supported by NIH Grants CA90970 and CA90970 SI (to R.K.).
PY - 2004/6/4
Y1 - 2004/6/4
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Cyclin D1
KW - Estrogen
KW - Estrogen receptor
KW - p21-activated kinase 1
UR - http://www.scopus.com/inward/record.url?scp=2942568370&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2942568370&partnerID=8YFLogxK
U2 - 10.1016/j.febslet.2004.04.071
DO - 10.1016/j.febslet.2004.04.071
M3 - Article
C2 - 15178330
AN - SCOPUS:2942568370
SN - 0014-5793
VL - 567
SP - 243
EP - 247
JO - FEBS Letters
JF - FEBS Letters
IS - 2-3
ER -