NCoA-1 (Kamei Y. et al., 1996)
Gene: SRC1 maps to 2p23 (Carapeti M. et al., 1998).
mRNA: sizes: approximately 5.5 kb and 7.5 kb in a variety of human tissues and cell lines (Anzick S.L. et al., 1997).
Protein: a 1,440-amino acids, 160 kDa coactivator that is required for full transcriptional activity of the steroid receptor superfamily. SRC-1 has a glutamine-rich region and a serine/threonine-rich region. SRC-1 enhances the transcriptional activity of ligand-bound progesterone receptor (
PgR) but does not alter the basal activity of the target promoter. SRC-1 also enhances
estrogen receptor (ER), glucocorticoid receptor, thyroid hormone receptor, and retinoid X receptor transcriptional activities through their cognate DNA response elements in the presence of hormone. Studies of the effects of SRC-1 on unrelated transactivators showed that the protein can enhance the transcriptional activities of SP1 and the chimeric Gal4-VP16 protein, but not those of E2F, E47, or CREB. Coexpression of SRC-1 with
PgR and
ER reversed the ability of ER to squelch activation by
PgR, suggesting that SRC-1 is a limiting factor necessary for efficient
PgR and
ER transactivation. A C-terminal form of SRC-1 containing the receptor-binding region acted as a dominant-negative repressor of endogenous SRC-1 function.
Cell lines:
- By Northern blot analysis, expression of SRC-1 mRNA remained relatively constant in four
ER-alpha-positive (BT-474, MCF-7, ZR-75-1, T-47D) and six
ER-alpha-negative (MDA-MB-361, -436, -468, -453, BT-20, and UACC-812) BCC lines (Anzick S.L. et al., 1997).
- MDA-MB-231 BCC were stably transfected with an inducible expression vector for
ER. In two cell clones, induction of
progesterone receptor (PgR) gene expression by ligand-bound
ER did not require demethylation of the
PgR CpG island. In contrast, induction of
PgR transcription was inhibited by blocking the interaction of
ER with SRC-1 (Ferguson A.T. et al., 1998).
Tumors:
- SRC-1 expression was determined using a semi-quantitative RT-PCR in 21 primary breast tumors, seven mammary tumor cell-lines, 12 fibroblast cultures, and six normal breast tissues. The highest levels of SRC-1 were observed in normal tissues, intermediate levels in tumor tissues, and the lowest levels in breast tumor cell-lines. There was no relationship between the levels of SRC-1 in these primary tumors and the proportion of tumor cells within the surgical samples, nor with
ER status. The median SRC-1 level was, however, lower in tumors from patients that did not respond to the antiestrogen tamoxifen (Berns E.M. et al., 1998).
- REA (repressor of estrogen receptor activity), encodes a 37-kDa protein that is an
ER-selective coregulator. It was shown to directly interact with ER and to competitively reverse SRC-1 enhancement of
ER activity (Montano M.M. et al., 1999).
