Structural determinants of DNA-binding specificity by steroid receptors.

Zilliacus, Johanna; Wright, Anthony P. H.; Carlstedt‐Duke, Jan; Gustafsson, Jan‐Åke

doi:10.1210/mend.9.4.7659083

Cited by 101 publications

(99 citation statements)

References 92 publications

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“…The AR protein has a modular structure composed of a C-terminal ligand binding domain (LBD) linked to a DNA binding domain (DBD) by a hinge region of 50 amino acids and a large, polymorphic N-terminal domain (NTD), important for transcriptional regulation (reviewed in Gelmann 2002, McEwan 2004. The DBD is a defining feature of the nuclear receptor superfamily and is necessary for specific DNA recognition and binding (reviewed in Zilliacus et al 1995. The DBD consists of eight conserved cysteine residues that co-ordinately bind two zinc ions, which are critical for the folding and function of the domain.…”

Section: Introductionmentioning

confidence: 99%

Intra-domain communication between the N-terminal and DNA-binding domains of the androgen receptor: modulation of androgen response element DNA binding

Brodie¹,

McEwan

2005

Journal of Molecular Endocrinology

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The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone. In vitro, two types of response element have been characterised -non-selective elements that bind the androgen, glucocorticoid and progesterone receptors, and androgen receptor-selective sequences. In the present study, the allosteric effects of DNA binding on the receptor amino-terminal domain (NTD) were studied. Binding to both types of DNA response element resulted in changes in the intrinsic fluorescence emission spectrum for four tryptophan residues within the AR-NTD and resulted in a more protease-resistant conformation. In binding experiments, it was observed that the presence of the AR-NTD reduced the affinity of receptor polypeptides for binding to both selective and non-selective DNA elements derived from the probasin, PEM and prostatin C3 genes respectively, without significantly altering the protein-base pair contacts. Taken together, these results highlight the role of intra-domain communications between the AR-NTD and the DNA binding domain in receptor structure and function.

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Section: Introductionmentioning

confidence: 99%

Intra-domain communication between the N-terminal and DNA-binding domains of the androgen receptor: modulation of androgen response element DNA binding

Brodie¹,

McEwan

2005

Journal of Molecular Endocrinology

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“…Structural studies of the ER␣ and GR DBDs complexed to DNA and in solution either lacked the comparable length CTE sequences in the expressed DBD constructs or the CTE was unstructured (32). Aside from an earlier report that sequences C-terminal to the core ER␣ DBD are important for DNA binding stability (47), no other biochemical data are available to suggest that the CTE of steroid receptors directly participates in DNA binding as it does with other nuclear receptors.…”

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confidence: 99%

“…Helix1 makes base-specific contacts in the major groove, while helix2 maintains the overall structural fold of the core DBD (32)(33)(34)(35)(36)(37)(38). Both biochemical and structural analyses of the nuclear receptor DBDs have shown that this domain is highly conserved across all nuclear receptors.…”

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confidence: 99%

The C-terminal Extension (CTE) of the Nuclear Hormone Receptor DNA Binding Domain Determines Interactions and Functional Response to the HMGB-1/-2 Co-regulatory Proteins

Melvin¹,

Roemer²,

Churchill³

et al. 2002

Journal of Biological Chemistry

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Previously, we and others reported that the high mobility group proteins, HMGB-1/-2, enhance DNA binding in vitro and transactivation in situ by the steroid hormone subgroup of nuclear receptors but did not influence these functions of class II receptors. We show here that the DNA binding domain (DBD) is sufficient to account for the selective influence of HMGB-1/-2 on the steroid class of receptors. Furthermore, the use of chimeric DBDs reveals that this selectivity is dependent on the C-terminal extension (CTE), amino acid sequences adjacent to the zinc finger core DBD. HMGB-1/-2 interact directly with the DBDs of steroid but not class II receptors, and this interaction requires the CTE. This in vitro interaction correlates with a requirement of the CTE for maximal HMGB-1/-2 enhancement of DNA binding in vitro and transcriptional activation in cells. Finally, class II receptor DBDs have a much higher intrinsic affinity for DNA than steroid receptor DBDs, and this affinity difference is also dependent on the CTE. These results reveal the importance of the steroid receptor CTE for DNA binding affinity and functional response to HMGB-1/-2.Nuclear hormone receptors comprise a superfamily of transcription factors that regulates diverse metabolic processes by binding to response elements in the enhancer regions of specific genes. This superfamily consists of three receptor subclasses: 1) the steroid hormone receptors for progesterone (PR) 1 , estrogen (ER), glucocorticoids (GR), androgens (AR), and mineralocorticoids (MR); 2) class II receptors for thyroid hormone (TR), retinoids (RAR and RXR), vitamin D3 (VDR), prostaglandins (PPAR), oxysterols, and bile acids; and 3) orphan receptors for which no endogenous ligand has been identified (1-4). Each of the receptor subclasses is characterized by a unique mechanism of action with respect to dimerization and DNA sequence recognition. Steroid receptors form homodimers that optimally recognize hexameric DNA elements arranged as inverted repeats separated by three unspecified base pairs. PR, GR, AR, and MR bind to the core hexamer AGAACA, whereas ER recognizes AGGTCA (2). Class II receptors preferentially function as heterodimers with RXR and recognize the AGGTCA hexamer arranged as direct repeats. Variable spacing between the direct repeats determines the RXR heterodimer binding specificity. Class II receptors, particularly TR, can also recognize an inverted repeat as homodimers, or half-sites as monomers. Orphan receptors can bind to the AGGTCA hexamer arranged either as a direct repeat, palindrome, or half-site as heterodimers with RXR, homodimers, or monomers (1, 5-7).DNA-bound nuclear receptors activate transcription through assembly of a coactivator protein complex (8 -10). Some of these coactivators possess enzyme activities that are thought to facilitate access of general transcription factors to chromatin templates (11,12). Additionally, the coactivator complex may serve as a protein bridge to facilitate assembly of the basal transcription apparatus (13, 14). We...

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“…Novel strategies to target AR directly through AR gene transcription and translation (10) or interfering in the interaction between AR and its co-factors and their downstream functions in prostate cancer cells have also been successfully attempted (15)(16)(17). AR activity is regulated by a host of factors including steroid hormones, thyroid hormones, vitamin D 3 (18), insulin-like growth factor I, insulin-like growth factor I receptor, keratinocyte growth factor, epidermal growth factor (19), interleukin-6 (20), and agents elevating and activating intracellular cAMP, G protein-coupled receptors, or a PKA signaling pathway (21,22). The details of the transcriptional/ translational mechanisms regulating AR within cancer cells remain unclear.…”

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confidence: 99%

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

Huang

Zhau

Chung

2010

Journal of Biological Chemistry

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A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-␤2-microglobulin monoclonal antibody (␤2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. ␤2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, ␤2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, ␤2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the ␤2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing ␤2M by ␤2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression. ␤2-Microglobulin (␤2M)3 is a co-receptor of a major histocompatibility complex class I antigen. ␤2M has been implicated in the regulation of the host immune mechanism and is essential for the recognition of foreign antigens by T-lymphocytes (1). Recent reports from our laboratory and others assigned additional biological functions to ␤2M as a diagnostic and prognostic indicator for multiple myeloma, prostate, and breast cancers (2-5); a growth factor and a signaling molecule (6, 7); a new androgen and androgen receptor (AR) target gene (8); and an attractive new therapeutic target for both liquid (9) and solid (10, 11) tumor malignancies. Blockade of ␤2M and its related signaling pathways by sequence-specific siRNA or antibody resulted in the inhibition of AR expression and activity and the induction of extensive prostate cancer cell death in vitro as well as prostate tumor regression in immune-compromised mice (7, 10). In addition, anti-␤2M monoclonal antibody (␤2M mAb) has been shown not to significantly affect the growth of normal cells, consistent with experimental observations where transgenic mice with a ␤2M deficit had normal organ function and life expectancy (9, 10, 12). Therefore, ␤2M and its signaling axis may offer an opportunity for improving the clinical targeting of prostate cancer.AR is a key growth and survival regulatory transcription factor for androgen target organs during normal development and neoplastic progression. Recognition of the importance of the AR signaling axis, particularly in castration-resistant prostate cancer, has prompted discoveries targeting androgen biosynthetic pathways using abiraterone as an agent for a Phase III trial...

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Structural determinants of DNA-binding specificity by steroid receptors.

Cited by 101 publications

References 92 publications

Intra-domain communication between the N-terminal and DNA-binding domains of the androgen receptor: modulation of androgen response element DNA binding

Intra-domain communication between the N-terminal and DNA-binding domains of the androgen receptor: modulation of androgen response element DNA binding

The C-terminal Extension (CTE) of the Nuclear Hormone Receptor DNA Binding Domain Determines Interactions and Functional Response to the HMGB-1/-2 Co-regulatory Proteins

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

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