Disease relevance of TGFB1I1

• Together, our data suggests that ARA55 may play very important roles in the progression of prostate cancer by the modulation of AR transactivation [1].
• BACKGROUND: To study the potential anti-androgenic activity of roxithromycin (RXM), we previously used human dermal fibroblasts transiently transfected with the expression vector of androgen receptor (AR) coactivator ARA55 as the in vitro model reflecting the end-organ hypersensitivity [2].

High impact information on TGFB1I1

• TRAF4 directly associated with the focal contact scaffold Hic-5, and the knockdown of either protein, disruption of the complex, or oxidant scavenging blocked cell migration [3].
• Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells [4].
• WASP, CrkL, syk, and paxillin-like Hic-5 incorporated to platelet cytoskeleton after platelet aggregation [5].
• Thus, CrkL is a novel molecular adapter for WASP and syk and may potentially transfer these molecules to the cytoskeleton through association with cytoskeletal proteins such as Hic-5 [5].
• Here, we showed that Hic-5 inhibits integrin-mediated cell spreading on fibronectin in a competitive manner with paxillin in NIH 3T3 cells [6].

Chemical compound and disease context of TGFB1I1

• Transient transfection assay in prostate cancer DU145 cells further demonstrates that ARA55 can enhance AR transcriptional activity in the presence of 1 nM dihydrotestosterone or its antagonists such as 100 nM 17beta-estradiol or 1 microM hydroxyflutamide [1].
• Only ARA70 and ARA55 were able to significantly increase the androgenic activity of hydroxyflutamide, the active metabolite of a widely-used antiandrogen for the treatment of prostate cancer [7].

Biological context of TGFB1I1

• Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator [8].
• Recently, we found that enforced expression of ARA55 inhibits transforming growth factor-beta-mediated up-regulation of Smad binding element-luciferase reporter activity in NRP-154 and NRP-152 rat prostate and LNCaP human prostate cell lines [9].
• These results suggest that Hic-5/ARA55 is required for optimal GR-mediated gene expression possibly by providing a scaffold that organizes or stabilizes coactivator complexes at some hormone-responsive promoters [10].
• Hydrogen peroxide-inducible clone-5 (Hic-5), belongs to the group III LIM domain protein family and contains four carboxyl-terminal LIM domains (LIM1-LIM4) [11].
• The ability of Hic-5/ARA55 to shuttle between the nuclear and cytoplasmic compartments was revealed on inhibition of nuclear export with leptomycin B [12].

Anatomical context of TGFB1I1

• LIM4 also functions as a nuclear matrix targeting sequence (NMTS) for Hic-5/ARA55, as it is both necessary and sufficient to target a heterologous protein to the nuclear matrix [11].
• Furthermore, a prostate stromal cell line, WPMY-1 cells, expresses Hic-5/ARA55, which is localized both at focal adhesion complexes and within the soluble cytoplasmic compartment [12].
• Hic-5/ARA55, a LIM domain-containing nuclear receptor coactivator expressed in prostate stromal cells [12].
• Hydrogen peroxide-inducible clone (Hic)-5 is induced during the senescent process in human fibroblasts, and the overexpression of Hic-5 induces a senescence-like phenotype [13].
• However, Hic-5 is not tyrosine phosphorylated either by the coexpressed FAK in COS cells or by integrin stimulation in 293T cells [13].

Associations of TGFB1I1 with chemical compounds

• Finally, the mechanism of Hic-5/ARA55 coactivator activity in WPMY-1 cells was revealed by chromatin immunoprecipitation analysis that showed its androgen-dependent recruitment to the promoter of the stromal androgen-responsive keratinocyte growth factor gene [12].
• Furthermore, overexpression of Hic-5 results in a decreased tyrosine phosphorylation of paxillin [13].
• In transiently transfected mammalian cells, overexpression of Hic-5 potentiated the activation of reporter genes by all steroid receptors, excluding the estrogen receptor [14].
• When platelets were stimulated with thrombin, collagen or the stable thromboxane A(2) analogue U46619, Hic-5 was markedly tyrosine-phosphorylated, in a manner dependent on integrin alphaIIbbeta3-mediated aggregation [15].
• With increasing amounts of transfected ARA55, AR transcriptional activity was enhanced by daidzein in a dose-dependent manner [16].

Physical interactions of TGFB1I1

• Yeast and mammalian two-hybrid systems and co-immunoprecipitation assays all prove ARA55 can bind to AR in a ligand-dependent manner [1].
• Here we show that Hic-5 binds to focal adhesion kinase (FAK) by its N-terminal domain, and is localized to focal adhesions by its C-terminal LIM domains [13].

Co-localisations of TGFB1I1

• In human embryonic kidney 293 cells, Hic-5 colocalizes with DAT at polarized sites and reduces DAT uptake activity through a mechanism involving a decrease in the cell-surface levels of the transporter [17].

Regulatory relationships of TGFB1I1

• Moreover, ARA55 also inhibits the induction of Smad-binding element 4-luciferase and 3TP-luciferase (a plasminogen activator inhibitor-1 (PAI-1) promoter construct) reporters by constitutively active (CA)-Smad3 in these cell lines [9].

Other interactions of TGFB1I1

• Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate [1].
• Here, we report mapping studies of Hic-5/ARA55 functional domains and establish that LIM3 and LIM4 are necessary for maximal effects on GR transactivation [11].
• Northern blot and polymerase chain reaction quantitation showed ARA55 can be expressed differently in normal prostate and prostate tumor cells [1].
• These findings suggest that putative functions of Hic-5 are the recruitment of FAK to focal adhesions and a competitive inhibition of tyrosine phosphorylation of paxillin [13].
• We first identified the AR-LBD coregulators ARA70, ARA55, and ARA54 [7].

Analytical, diagnostic and therapeutic context of TGFB1I1

• ARA55 expression level in HRPC specimens was significantly lower than that in previously untreated prostate cancer (P = 0.02) or BPH (P = 0.005) samples using quantitative PCR [18].
• In biochemical fractionations and indirect immunofluorescence assays, a fraction of endogenous Hic-5 in REF-52 cells and transiently expressed Hic-5 in Cos-1 cells was associated with the nuclear matrix [14].
• Fluorescent in situ hybridization by using a human Hic-5 specific probe localized the gene to human chromosome 16p11 [19].
• Molecular cloning of human Hic-5, a potential regulator involved in signal transduction and cellular senescence [19].
• In this study we examined the expression of the LIM proteins paxillin and Hic-5 in adult human tissues by immunohistochemistry and immunoblotting [20].

References