Distinct Recognition Modes of FXXLF and LXXLL Motifs by the Androgen Receptor

Dubbink, Hendrikus J.; Hersmus, Remko; Verma, Chandra; Korput, Hetty A. G. M. van der; Berrevoets, Cor; Tol, Judith van; Made, Angelique C. J. Ziel-van der; Brinkmann, Albert O.; Pike, Ashley C.W.; Trapman, Jan

doi:10.1210/me.2003-0375

Cited by 103 publications

(131 citation statements)

References 59 publications

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“…This model is focused on the LXXLL motif-mediated interactions between PGC-1␣ and NRs, and the potential involvements of different regions of two proteins for additional interactions are not included. thermore, additional structures containing the Leu/Phe or Leu/ Met swapping within the NR-box were observed for their complexes with androgen receptor, ER␣, and retinoid X receptor ␣ (56,(72)(73)(74)(75). However, unlike NR2 and NR3, PGC-1␣ NR1 does not fall into any distinct class of the NR-boxes.…”

Section: Discussionmentioning

confidence: 99%

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

Rha

Shoelson

et al. 2009

Journal of Biological Chemistry

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Hepatocyte nuclear factor 4␣ (HNF4␣) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4␣ interacts, peroxisome proliferation-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/ p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1␣ recruitment, we have determined the crystal structure of HNF4␣ in complex with a fragment of PGC-1␣ containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4␣ toward the LXXLL motifs of PGC-1␣ could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators.

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Section: Discussionmentioning

confidence: 99%

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

Rha

Shoelson

et al. 2009

Journal of Biological Chemistry

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“…This region shows high homology between REA and PHB, and contains an FxxIL motif that is similar to motifs recently shown to have high affinity for the AR (Dubbink et al, 2004;Hur et al, 2004). We therefore mutated this motif to determine whether it is required for in vivo repression of AR function by PHB.…”

Section: Phb Inhibits Ar Activitymentioning

confidence: 99%

Prohibitin, a protein downregulated by androgens, represses androgen receptor activity

et al. 2006

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Prohibitin (PHB) is a cell cycle regulatory protein, known to repress E2F1-mediated gene activation via recruitment of transcriptional regulatory factors such as retinoblastoma and histone deacetylase 1 (HDAC1). We previously identified PHB as a target protein of androgen signaling in prostate cancer cells and showed that downregulation of PHB is required for androgen-induced cell cycle entry in these cells. We now present evidence that PHB, which has 54% homology at the protein level to the oestrogen receptor corepressor REA (repressor of oestrogen receptor activity), can repress androgen receptor (AR)-mediated transcription and androgen-dependent cell growth. Depletion of endogenous PHB resulted in an increase in expression of the androgen-regulated prostatespecific antigen gene. The repression appears to be specific to androgen and closely related receptors, as it is also evident for the glucocorticoid and progesterone, but not oestrogen, receptors. In spite of interaction of PHB with HDAC1, HDAC activity is not required for this repression. Although AR and PHB could be co-immunoprecipitated, no direct interaction was detectable, suggesting that PHB forms part of a repressive complex with the AR. Competition with the co-activator SRC1 further suggests that formation of a complex with AR, PHB and other cofactors is the mechanism by which repression is achieved. It appears then that repression of AR activity is one mechanism by which PHB inhibits androgendependent growth of prostate cells. Further, this study implies that the AR itself could, by mediating downregulation of a corepressor, be involved in the progression of prostate tumours to the hormone refractory stage.

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“…However, the AR is idiosyncratic in that it appears to interact preferentially with phenylalanine-rich motifs, found in several AR co-activators including ARA70, FHL2 and gelsolin (Hsu et al, 2003;Dubbink et al, 2004;Hur et al, 2004;van de Wijngaart et al, 2006). We therefore next looked at whether the mutant receptors showed altered relative affinity for different interaction motifs in the presence of alternative ligands.…”

Section: Discussionmentioning

confidence: 99%

“…Many co-activators, including the p160 protein SRC-1, interact with the LBD of nuclear receptors via conserved, helical leucine-rich motifs (LxxLL, L, leucine and x, any amino acid (reviewed in McKenna et al, 1999)). Recently the AR LBD has also been demonstrated to interact with similar phenylalanine-rich motifs (Hsu et al, 2003;Dubbink et al, 2004;Hur et al, 2004). However, SRC-1 and other co-activators can also interact with and promote activity of AF1 (reviewed in McEwan, 2004).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression

2007

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Prostate tumour growth depends on androgens; hence treatment includes androgen ablation and anti-androgens. Eventually tumours progress and in approximately 30% of patients this is associated with mutation of the androgen receptor. Several receptor variants associated with advanced disease show promiscuous activation by other hormones and anti-androgens. Such loss of specificity could promote receptor activation, hence tumour growth, in the absence of conventional ligands, explaining therapy failure. We aimed to elucidate mechanisms by which alternative ligands promote receptor activation. The three most commonly identified variants in tumours (with amino-acid substitutions H874Y, T877A and T877S) and wild-type receptor showed differences in co-activator recruitment dependent upon ligand and the interaction motif utilized. Co-expression and knockdown of co-activators that bind via leucine or phenylalanine motifs, combined with chromatin immunoprecipitation and quantitative PCR, revealed these preferences extend to co-activator recruitment in vivo and affect receptor activity at the transcriptional level, with subsequent effects on target gene regulation. The findings suggest that mutant receptors, activated by alternative ligands, drive growth via different mechanisms to androgenactivated wild-type receptor. Tumours may hence behave differently dependent upon any androgen receptor mutation present and what ligand is driving growth, as distinct subsets of genes may be regulated.

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Distinct Recognition Modes of FXXLF and LXXLL Motifs by the Androgen Receptor

Cited by 103 publications

References 59 publications

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

Multiple Binding Modes between HNF4α and the LXXLL Motifs of PGC-1α Lead to Full Activation

Prohibitin, a protein downregulated by androgens, represses androgen receptor activity

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression

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