A ligand-dependent bipartite nuclear targeting signal in the human androgen receptor. Requirement for the DNA-binding domain and modulation by NH2-terminal and carboxyl-terminal sequences.

Zhou, Zhong Xun; Sar, Madhabananda; Simental, Jorge A.; Lane, Malcolm V.; Wilson, Elizabeth M.

doi:10.1016/s0021-9258(17)36806-0

Cited by 270 publications

(29 citation statements)

References 56 publications

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“…AR in the cytoplasm forms a complex with chaperone proteins such as heat-shock protein 90 (HSP90), HSP70, and HSP56 (Picard and Yamamoto 1987; Hager et al 2000; Pratt et al 2004). Ligand binding leads to a conformational change of its receptor followed by revealing the NLS (Simental et al 1991; Zhou et al 1994; Gelmann 2002). Many studies have suggested that exposed NLS of the cytoplasmic cargo protein is recognized by the importin family that mediates translocation to the nucleus through the nuclear complex, and the direct binding of Ran GTP to importin-cargo complex releases the cargo into the nucleoplasm (Picard and Yamamoto 1987; Poukka et al 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Steroid/nuclear receptors can be divided into three categories based on their unliganded distribution: those primarily in the nucleus (estrogen receptor and thyroid hormone receptor), those in the cytoplasm (glucocorticoid receptor and retinoic acid receptor), and those with a mixed distribution in both the cytoplasm and nucleus (mineralocorticoid receptor, progesterone receptor, and vitamin D receptor). AR without binding ligands is primarily located in the cytoplasm (Zhou et al 1994; Georget et al 1997) and is thought to be in an inactive state in which it is bound to chaperones, including heat-shock proteins (hsp56, hsp90, and hsp70) (Picard and Yamamoto 1987; Yeh et al 1999; Pratt et al 2004). It is well conceived that androgen binding induces conformational changes in AR, but whether the same complex responsible for unliganded AR undergoes nuclear translocation is not clear (Kumar et al 2006).…”

mentioning

confidence: 99%

“…The NLS, once exposed, can be recognized by importin α with importin β, which mediates AR translocation from the cytoplasm to nucleus (Kumar et al 2006). Within the nucleus, AR forms, homodimer, and the molecular basis by which AR mediates assembly of the transcription complex have been emerging recently (Zhou et al 1994; Tomura et al 2001; Black and Paschal 2004).…”

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confidence: 99%

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A Differential Ligand-mediated Response of Green Fluorescent Protein-tagged Androgen Receptor in Living Prostate Cancer and Non-prostate Cancer Cell Lines

Nakauchi

Matsuda

Ochiai

et al. 2007

J Histochem Cytochem.

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S U M M A R Y Androgen has been shown to promote the proliferation of prostate cancer through the action of the androgen receptor (AR). Mutation (T877A) of the AR gene found in an androgen-sensitive prostate cancer cell line, LNCaP, has been postulated to be involved in hypersensitivity and loss of specificity for androgen. In the present study, trafficking of AR and AR (T877A) in living prostate and non-prostate cancer cell lines under high and low concentrations of androgen and antiandrogen was investigated by tagging green fluorescent protein (GFP) to the receptors. In the presence of a high concentration of androgen, AR-GFP localized in the nucleus by forming discrete clusters in all cell lines. AR (T877A)-GFP was also translocated to the nucleus in LNCaP and COS-1 cells by the addition of a high concentration of androgen. In contrast, in the presence of a low concentration of androgen, the translocation of AR-GFP and AR (T877A)-GFP was observed in LNCaP cells, but not in COS-1 cells. Upon the addition of antiandrogen, AR-GFP was translocated to the nucleus but did not form subnuclear foci in both COS-1 and LNCaP cells, whereas AR (T877A)-GFP in both cells was translocated to the nucleus with subnuclear foci. The present study demonstrates the differential response of nuclear trafficking of AR and its mutant in prostate cancer cell lines and COS cells, and the subcellular and subnuclear compartmentalization provide important information on the sensitivity of the AR mutation. (J Histochem Cytochem 55:535-544, 2007)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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A Differential Ligand-mediated Response of Green Fluorescent Protein-tagged Androgen Receptor in Living Prostate Cancer and Non-prostate Cancer Cell Lines

Nakauchi

Matsuda

Ochiai

et al. 2007

J Histochem Cytochem.

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“…It is established that canonical AR-fl utilizes the classical importin α /β nuclear import mechanism where the importin-α binds to the NLS of AR protein followed by importin β binding, forming a trimeric (cargo-NLS/ importin-α / importin-β) complex in the cytoplasm which enters the nucleus through the nuclear pore complex (NPC) using the Ran-GTP (Pemberton and Paschal, 2005). To identify the mechanisms mediating AR-V7 nuclear import, we examined the involvement of the MT-transport system and the importin-α /β -Ran-GTP pathway (Darshan et al, 2011; Jenster et al, 1993; Kaku et al, 2008; Thadani-Mulero et al, 2014; Zhou et al, 1994; Zhu et al, 2010). We analyzed the translocation kinetics of each variant by live-cell time-lapse imaging using chemical probes that disrupt MTs (docetaxel) or importin-β (importazole) (Figure 1D and S1B-S1D).…”

Section: Resultsmentioning

confidence: 99%

AR-V7 exhibits non-canonical mechanisms of nuclear import and chromatin engagement in Castrate-Resistant Prostate Cancer

Jamalruddin

et al. 2021

Preprint

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Expression of the AR splice variant, AR-V7, in prostate cancer is correlated with poor patient survival and resistance to AR targeted therapies and taxanes. Currently, there is no specific inhibitor of AR-V7, while the molecular mechanisms regulating its biological function are not well elucidated. Here we report that AR-V7 has unique biological features that functionally differentiate it from canonical AR-fl or from the second most prevalent variant, AR-v567. First, AR-V7 exhibits fast nuclear import kinetics via a pathway distinct from the nuclear localization signal dependent importin-α/β pathway used by AR-fl and AR-v567. We also show that the dimerization box domain, known to mediate AR dimerization and transactivation, is required for AR-V7 nuclear import but not for AR-fl. Once in the nucleus, AR-V7 is transcriptionally active, yet exhibits unusually high intranuclear mobility and transient chromatin interactions, unlike the stable chromatin association of liganded AR-fl. The high intranuclear mobility of AR-V7 together with its high transcriptional output, suggest a Hit-and-Run mode of transcription. Our findings reveal unique mechanisms regulating AR-V7 activity, offering the opportunity to develop selective therapeutic interventions.

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“…Furthermore, we have shown in this study that nuclear localization of PARP7 is required for AR ADP-ribosylation. Given that androgen binding to AR drives its import into the nucleus [33][34][35] where PARP7 localizes, it is logical that androgen-dependence of AR ADP-ribosylation is in part explained by the increased concentration of AR in the nucleus for PARP7 to act on. Second, PARP7 is a direct AR target gene that is induced by androgen treatment [7,8].…”

Section: Discussionmentioning

confidence: 99%

PARP7 mono-ADP-ribosylates the Agonist Conformation of the Androgen Receptor in the Nucleus

Kamata

Yang

Paschal

2021

Preprint

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We recently described a signal transduction pathway that contributes to AR regulation based on site-specific ADP-ribosylation by PARP7, a mono-ADP-ribosyltransferase implicated in several human cancers. ADP-ribosylated AR is specifically recognized by PARP9/DTX3L, a heterodimeric complex that contains an ADP-ribose reader (PARP9) and a ubiquitin E3 ligase (DTX3L). Here, we have characterized the cellular and biochemical requirements for AR ADP-ribosylation by PARP7. We found that the reaction requires nuclear localization of PARP7 and an agonist-induced conformation of AR. PARP7 contains a Cys3His1-type zinc finger (ZF), which we found is critical for AR ADP-ribosylation. The Parp7 ZF is required for efficient nuclear localization by the nuclear localization signal (NLS) encoded in PARP7, but rescue experiments indicate the ZF makes a contribution to AR ADP-ribosylation that is transport-independent. ZF structure appears to be dispensable for PARP7 catalytic activity and for PARP7 binding to AR. Androgen induction of the MYBPC1 gene is regulated by AR and PARP7, and we determined that the ZF is required for the PARP7 transcriptional effect on MYBPC1. Our data indicate the PARP7 ZF plays an important role in modulating the subcellular localization of PARP7 and its capacity to ADP-ribosylate and promote AR-dependent transcription.

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A ligand-dependent bipartite nuclear targeting signal in the human androgen receptor. Requirement for the DNA-binding domain and modulation by NH2-terminal and carboxyl-terminal sequences.

Cited by 270 publications

References 56 publications

A Differential Ligand-mediated Response of Green Fluorescent Protein-tagged Androgen Receptor in Living Prostate Cancer and Non-prostate Cancer Cell Lines

A Differential Ligand-mediated Response of Green Fluorescent Protein-tagged Androgen Receptor in Living Prostate Cancer and Non-prostate Cancer Cell Lines

AR-V7 exhibits non-canonical mechanisms of nuclear import and chromatin engagement in Castrate-Resistant Prostate Cancer

PARP7 mono-ADP-ribosylates the Agonist Conformation of the Androgen Receptor in the Nucleus

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