Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

Cronauer, Marcus V.; Ince, Yasemin; Engers, Rainer; Rinnab, L.; Weidemann, Wolfgang; Suschek, Christoph V.; Burchardt, Martin; Kleinert, Hartmut; Wiedenmann, Jörg; Sies, Helmut; Ackermann, R.; Kröncke, Klaus‐Dietrich

doi:10.1038/sj.onc.1209984

Cited by 57 publications

(59 citation statements)

References 47 publications

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“…The inhibitory effect of NO on the DNA-binding of zinc-finger proteins is most likely due to a reversible S-nitrosation of cysteine residues of the two cys4-type zinc fingers, which are essential for DNA-binding . Although NO inhibits DNA-binding activity of the nuclear steroid hormone receptors, it does not affect intracellular receptor protein levels or its nuclear import as recently shown for the AR (Cronauer et al, 2006). The nuclear localization signal of EcR located in the CD-domain is functional in the absence of zinc-fingers (Gwozdz et al, 2007), which confirms that NO does not change nuclear import.…”

Section: No As a Tool To Study Intranuclear Localization Of Nuclear Rsupporting

confidence: 60%

Nuclear localization and DNA binding of ecdysone receptor and ultraspiracle

Cronauer¹,

Braun²,

Tremmel³

et al. 2007

Arch Insect Biochem Physiol

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The Ecdysone receptor (EcR) is distributed between cytoplasm and nucleus in CHO cells. Nuclear localization is increased by the ligand Muristerone A. The most important heterodimerization partner Ultraspiracle (Usp) is localized predominantly in the nucleus. We used the diethylentriamine nitric oxide adduct DETA/NO, which releases NO and destroys the zinc-finger structure of nuclear receptors, to investigate whether nuclear EcR and Usp interact with DNA. If expressed separately, Usp and EcR in the absence of hormone do not interact with DNA. The hormone-induced increase in nuclear EcR is due to enhanced DNA binding. In the presence of Usp, EcR is shifted nearly quantitatively into the nucleus. Only a fraction (approximately 30%) of the heterodimer is sensitive to DETA/NO. Interaction of the heterodimer with DNA is mediated mainly by the C-domain of EcR. Deletion of the DNA-binding domain of Usp only slightly reduces nuclear localization of EcR/Usp, although the nuclear localization signal of Usp is not present anymore. The results indicate that EcR and Usp can enter the nucleus independently, but cotransport of both receptors mediated by dimerization via the ligand binding domains is possible even in the absence of hormone.

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Section: No As a Tool To Study Intranuclear Localization Of Nuclear Rsupporting

confidence: 60%

Nuclear localization and DNA binding of ecdysone receptor and ultraspiracle

Cronauer¹,

Braun²,

Tremmel³

et al. 2007

Arch Insect Biochem Physiol

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“…AR-positive LNCaP cells were routinely transfected with the pGL3E-Probasin reporter (200 ng/well) as previously described (22). pGL4hRluc used to correct for transfection efficiency was co-transfected in every experiment (80 ng/well).…”

Section: Methodsmentioning

confidence: 99%

Inability of NCoR/SMRT to repress androgen receptor transcriptional activity in prostate cancer cell lines

Laschak

Bechtel²,

Spindler³

et al. 2011

Int J Mol Med

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Abstract. The molecular mechanisms leading to castrationresistant prostate cancer (CRPC) are poorly understood. Among several mechanisms leading to CRPC growth a dysregulation of androgen receptor (AR) co-regulators (i.e. up-regulation of co-activators or down-regulation of co-repressors) is discussed. There are numerous reports demonstrating an increased expression of co-activators during prostate cancer progression. On the contrary, the impact of co-repressors on tumor growth and development is less clear. In this study we compared the effects of two known co-repressors, NCoR and SMRT, on AR transcriptional activity in prostate cancer (PCa) cell lines and compared them to that in COS-1 cells. Interestingly, we found that NCoR/SMRT overexpression did not repress AR-dependent gene expression in the PCa cell lines, but rather activated it. This finding is probably due to an impaired AR-co-repressor interaction in the prostate cancer cell lines. In conclusion, we provide evidence that up-regulation of NCoR or SMRT may increase transcriptional activity of the AR in a cell type-specific context.

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“…Higher levels of NO· can be produced by an inducible nitric oxide synthase (iNOS, also known as NOS2) in different cell types, but mainly in macrophages, upon infection to kill pathogens (reviewed in reference 9). The higher levels of NO· produced by iNOS have been implicated in various human inflammatory diseases and neurodegenerative diseases (reviewed in references 9 and 12) and in chronic inflammation-related tumorigenesis (18,33). Recent studies have also shown that chemical-generated higher levels of exogenous NO· can induce tumor cell apoptosis in vitro and in animal studies (37; reviewed in reference 1), raising interests in therapeutic exploration of NO·-releasing reagents as antitumor prodrugs.…”

mentioning

confidence: 99%

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

Mocca

Wang

2012

J Bacteriol

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In mammalian cells, nitric oxide (NO·) is an important signal molecule with concentration-dependent and often controversial functions of promoting cell survival and inducing cell death. An inducible nitric oxide synthase (iNOS) in various mammalian cells produces higher levels of NO· from L-arginine upon infections to eliminate pathogens. In this study, we reveal novel pathogenic roles of NO· generated by bacteria in bacterium-host cell cocultures using Moraxella catarrhalis, a respiratory tract disease-causing bacterium, as a biological producer of NO·. We recently demonstrated that M. catarrhalis cells that express the nitrite reductase (AniA protein) can produce NO· by reducing nitrite. Our study suggests that, in the presence of pathophysiological levels of nitrite, this opportunistic pathogen hijacks host cell signaling and modulates host gene expression through its ability to produce NO· from nitrite. Bacterium-generated NO· significantly increases the secretion of tumor necrosis factor alpha (TNF-␣) and modulates the expression of apoptotic proteins, therefore triggering host cell programmed death partially through TNF-␣ signaling. Furthermore, our study reveals that bacterium-generated NO· stalls host cell division and directly results in the death of dividing cells by reducing the levels of an essential regulator of cell division. This study provides unique insight into why NO· may exert more severe cytotoxic effects on fast growing cells, providing an important molecular basis for NO·-mediated pathogenesis in infections and possible therapeutic applications of NO·-releasing molecules in tumorigenesis. This study strongly suggests that bacterium-generated NO· can play important pathogenic roles during infections. In mammalian cells, nitric oxide (NO·) is a highly reactive and diffusible signaling molecule that plays key roles in modulating both physiological and pathological processes, such as immune response, cell survival, and cell death (reviewed in references 8 and 36). The diverse functions of NO· are often determined by its concentration or its source of production. Low levels of endogenous NO· are produced from L-arginine by constitutively expressed nitric oxide synthase in neuronal cells (nNOS, also known as NOS1) and endothelial cells (eNOS, also known as NOS3) to mediate normal physiological processes. Higher levels of NO· can be produced by an inducible nitric oxide synthase (iNOS, also known as NOS2) in different cell types, but mainly in macrophages, upon infection to kill pathogens (reviewed in reference 9). The higher levels of NO· produced by iNOS have been implicated in various human inflammatory diseases and neurodegenerative diseases (reviewed in references 9 and 12) and in chronic inflammation-related tumorigenesis (18, 33). Recent studies have also shown that chemical-generated higher levels of exogenous NO· can induce tumor cell apoptosis in vitro and in animal studies (37; reviewed in reference 1), raising interests in therapeutic exploration of NO·-releasing reagents as antitumor...

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Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

Cited by 57 publications

References 47 publications

Nuclear localization and DNA binding of ecdysone receptor and ultraspiracle

Nuclear localization and DNA binding of ecdysone receptor and ultraspiracle

Inability of NCoR/SMRT to repress androgen receptor transcriptional activity in prostate cancer cell lines

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

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