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Coactivation of estrogen receptor alpha by the DEAD-box RNA helicases p68 and p72 and its role in breast cancer
Breast Cancer Research volume 10, Article number: P16 (2008)
We have previously demonstrated that the DEAD-box RNA helicase p68 is an important regulator of gene expression [1, 2], whilst other groups have shown that p68 interacts with and coactivates estrogen receptor alpha (ERα) [3, 4]. The main focus of our project is to investigate the molecular mechanism of ERα coactivation by p68 and to examine the potential consequences for breast cancer development.
We have established that the interaction of p68 and ERα requires the DNA binding domain of ERα and the C terminus of p68. Importantly, this region of p68 lies outside the conserved helicase core and was previously shown by us to be essential for transcriptional regulation by p68. Additionally, coactivation of ERα by p68 requires the ligand binding/AF2 region of ERα and is consistent with the model that p68 is recruited to ERα-responsive promoters in response to estrogen . We have also shown that p72, a helicase that is very highly related to p68 and that had previously been suggested to act in an analogous fashion to p68 , poorly coactivates ERα in standard transcriptional coactivation assays, using ER-responsive promoters. This is underscored by our finding that overexpression of p68, but not of p72, in cell lines results in stimulation of expression of physiological target genes of ERα.
Interestingly, siRNA-mediated knockdown of endogenous p68 has little effect on the expression of ERα target genes. This observation is consistent with the idea that p68 has little effect on ERα function physiologically, but that the elevated p68 levels found in tumours may stimulate ERα-mediated gene expression in a pathological context. Strikingly, however, in contrast to p68, knockdown of endogenous p72 results in a marked inhibition of both baseline and estrogen stimulated-expression of these genes. These findings suggest, firstly, that p72 is important physiologically for ERα activity in the cell and, secondly, that p68 and p72 may be acting in an opposing rather than analogous fashion (as had been previously suggested ). Moreover, our preliminary data suggest that overexpression of p68 in cells may additionally coactivate ERα in an estrogen-independent manner, a finding that may have implications in the development of resistance to endocrine therapies.
We are currently developing inducible p68/p72 overexpression and siRNA cell lines with a view to examining the effect of augmenting or suppressing p68/p72 expression in mouse xenograft models. Additionally we are screening a large panel of breast cancers to examine p68 and p72 expression/localisation in the context of ERα expression.
Bates GJ, Nicol SM, Wilson BJ, Jacobs AM, Bourdon JC, Wardrop J, Gregory DJ, Lane DP, Perkins ND, Fuller-Pace FV: The DEAD box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor. EMBO J. 2005, 24: 543-553. 10.1038/sj.emboj.7600550.
Wilson BJ, Bates GJ, Nicol SM, Gregory DJ, Perkins ND, Fuller-Pace FV: The p68 and p72 DEAD box RNA helicases interact with HDAC1 and repress transcription in a promoter-specific manner. BMC Mol Biol. 2004, 5: 11-10.1186/1471-2199-5-11.
Watanabe M, Yanagisawa J, Kitagawa H, Takeyama K, Ogawa S, Arao Y, Suzawa M, Kobayashi Y, Yano T, Yoshikawa H, Masuhiro Y, Kato S: A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA. EMBO J. 2001, 20: 1341-1352. 10.1093/emboj/20.6.1341.
Métivier R, Penot G, Hübner MR, Reid G, Brand H, Kos M, Gannon F: Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell. 2003, 115: 751-763. 10.1016/S0092-8674(03)00934-6.
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Fuller-Pace, F., Ahamed, E., Wortham, N. et al. Coactivation of estrogen receptor alpha by the DEAD-box RNA helicases p68 and p72 and its role in breast cancer. Breast Cancer Res 10, P16 (2008). https://doi.org/10.1186/bcr1900
- Estrogen Receptor Alpha
- Analogous Fashion
- siRNA Cell
- Helicase Core
- Coactivates Estrogen Receptor