Multiple Receptor Domains Interact to Permit, or Restrict, Androgen-specific Gene Activation

Scheller, Arno; Hughes, Elizabeth D.; Golden, Kish L.; Robins, Diane M.

doi:10.1074/jbc.273.37.24216

Cited by 51 publications

(51 citation statements)

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“…It is true that androgen receptors and glucocorticoid receptors can bind to similar responsive elements on DNA (Van Dijck et al, 1989). However, there are also distinct differences between the two receptors which contribute to receptor-selective transcriptional regulation (Rundlett and Miesfeld, 1995;Claessens et al, 1996;Scheller et al, 1998). It is interesting that, in contrast to the findings of Derfoul et al (1998), in the current investigations androgens are potent inhibitors of the expression of the β1-subunit of Na + ,K + -ATPase in LNCaP cells.…”

Section: Regulation Of Expression Of Na + K + -Atpase In Prostate Cacontrasting

confidence: 50%

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

et al. 1999

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The β1-subunit of Na + ,K + -ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of androgens. Down-regulation of the β1-subunit was initiated at concentrations between 0.01 n M and 0.03 n M of the synthetic androgen R1881 after relatively long incubation times (> 24 h). Using polyclonal antibodies, the concentration of β1-subunit protein, but not of the α1-subunit protein, was markedly reduced in androgen-dependent human prostate cancer cells (LNCaP-FGC) cultured in the presence of androgens. In line with these observations it was found that the protein expression of total Na + ,K + -ATPase in the membrane (measured by 3 H-ouabain binding) was also markedly decreased. The main function of Na + ,K + -ATPase is to maintain sodium and potassium homeostasis in animal cells. The resulting electrochemical gradient is facilitative for transport of several compounds over the cell membrane (for example cisplatin, a chemotherapeutic agent experimentally used in the treatment of hormone-refractory prostate cancer). Here we observed that a ouabain-induced decrease of Na + ,K + -ATPase activity in LNCaP-FGC cells results in reduced sensitivity of these cells to cisplatin-treatment. Surprisingly, androgen-induced decrease of Na + ,K + -ATPase expression, did not result in significant protection against the chemotherapeutic agent. © 1999 Cancer Research Campaign

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Section: Regulation Of Expression Of Na + K + -Atpase In Prostate Cacontrasting

confidence: 50%

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

et al. 1999

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“…Thus SRC1 can interact with both termini of the AR, in common with several other cofactors including CBP (Frønsdal et al 1998). The N and C termini of AR have long been known to interact (Zhou et al 1995, Doesburg et al 1997, Ikonen et al 1997, Berrevoets et al 1998, Langley et al 1998, Scheller et al 1998, He et al 2002 and this interaction is believed to be necessary for maximal AR activity on certain promoters, as demonstrated by mutational analysis of the AR on selective versus non-selective androgen response elements (ARE) (Callewaert et al 2003). One hypothesis is that SRC1 or other coactivators may act as bridging factors between the termini or stabilise the N/Cterminal interaction, but this has not been possible to prove directly.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate.

Powell

Christiaens²,

Voulgaraki³

et al. 2004

Endocr Relat Cancer

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The androgen receptor (AR) is a member of the nuclear receptor superfamily. These ligand-activated transcription factors usually contain two activation functions, a ligand-independent activation function 1(AF1) in the divergent N-terminal domain and a ligand-dependent AF2 in the more conserved Cterminal ligand-binding domain. To promote transcription from target promoters, DNA-bound nuclear receptors recruit coactivator proteins that promote transcription by modifying histones within nucleosomes, resulting in altered topology of chromatin to allow access of the basal transcriptional machinery, or stabilising the pre-initiation complex. It is well known that most coactivators interact with AF2 of many nuclear receptors via conserved, helical LxxLL motifs (where L is leucine and x is any amino acid). The AF2 of the AR is very weak, but we were able to demonstrate that its intrinsic liganddependent activity is potentiated by steroid receptor coactivator-1 (SRC1) and that this region interacts with coactivators via LxxLL motifs. However, a mutant SRC1 coactivator with no functional LxxLL motifs was still able to potentiate AR activity. We found that SRC1 can also be recruited to (and increase activity of) AF1 of the AR via a conserved, glutamine-rich region. Point mutations within this region abolish SRC1 interaction with AF1 and also abolish or severely impair its ability to potentiate AR activity on all promoters tested. Thus the AR interacts with SRC1 via two different regions and the AF1 interaction is functionally the more important, although the contribution of the two interactions varies in a promoter-dependent fashion. SRC1 then potentiates receptor activity via recruitment of CBP/p300, a histone acetyltranferase. This is important in the context of prostate cancer as SRC1 and other coactivators including CBP are coexpressed with AR in the luminal epithelial cells of the prostate, where over 90% of prostate tumours arise. There is a need for effective second-line prostate cancer therapy aimed at blocking the AR pathway when anti-androgen therapy has failed. Since there is growing evidence that nuclear receptor cofactors may be implicated in the progression of hormone-dependent tumours to hormoneindependent states, novel targets could include the interaction of AR with coactivator proteins. We suggest that the N-terminal interaction would be a more specific and effective target in the case of prostate cancer than the LxxLL/AF2 interaction.

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“…Nevertheless, the hormones for each receptor elicit distinct physiological functions. Multiple mechanisms have been demonstrated in several cases to enforce steroid-specific gene activation, including subtle preferences in DNA-binding site (3)(4)(5), domain interactions within and between receptors that enhance cooperative function (6,7), and differential protein-protein interactions of the receptors with other regulatory factors (8,9). The latter may include interactions with other DNAbinding factors (e.g.…”

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confidence: 99%

Oct-1 Preferentially Interacts with Androgen Receptor in a DNA-dependent Manner That Facilitates Recruitment of SRC-1

González

Robins

2001

Journal of Biological Chemistry

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Gene regulation by steroid hormone receptors depends on the particular character of the DNA response element, the array of neighboring transcription factors, and recruitment of coactivators that interface with the transcriptional machinery. We are studying these complex interactions for the androgen-dependent enhancer of the mouse sex-limited protein (Slp) gene. This enhancer has, in addition to multiple androgen receptor (AR)-binding sites, a central region (FPIV) with a binding site for the ubiquitous transcription factor Oct-1 that appears crucial for hormonal regulation in vivo. To examine the role of Oct-1 in androgen-specific gene activation, we tested the interaction of Oct-1 with AR versus glucocorticoid receptor (GR) in vivo and in vitro. Oct-1 coimmunoprecipitated from cell lysates with both AR and GR, but significant association with AR required both proteins to be DNA-bound. This was confirmed by sensitivity of the protein association to treatment with ethidium bromide or micrococcal nuclease. Addition of DNA to micrococcal nuclease-treated samples restored interaction, even when binding sites were on separate DNA molecules, suggesting association was due to direct protein-protein interaction and not indirect tethering via the DNA. AR/GR chimeras revealed that interaction of the N and C termini of AR was required to communicate the DNA-bound state that enhances interaction with Oct-1. Protease digestion assays of hormone-bound receptors revealed further conformational changes in the ligand binding domain of AR, but not GR, upon DNA binding. Furthermore, these conformational changes led to increased interaction with the coactivator SRC-1, via the NID 4 domain, suggesting DNA binding facilitates recruitment of SRC-1 by the AR-Oct-1 complex. Altogether, these results suggest that the precise arrangement of binding sites in the Slp enhancer ensures proper hormonal response by imposing differential interactions between receptors and Oct-1, which in turn contributes to SRC-1 recruitment to the promoter.

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Multiple Receptor Domains Interact to Permit, or Restrict, Androgen-specific Gene Activation

Cited by 51 publications

References 50 publications

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in prostate.

Oct-1 Preferentially Interacts with Androgen Receptor in a DNA-dependent Manner That Facilitates Recruitment of SRC-1

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