RNA diversity has profound effects on the translation of neuronal nitric oxide synthase

Wang, Yan; Newton, Dwight F.; Robb, G. Brett; Kau, Cheng-Lin; Miller, Tricia L.; Cheung, Anthony H.; Hall, Anne V.; VanDamme, Suzannah; Wilcox, Josiah N.; Marsden, Philip A.

doi:10.1073/pnas.96.21.12150

Cited by 173 publications

(163 citation statements)

References 33 publications

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“…The quantitative discrepancy between RNA and protein levels can be best explained by the fact that RNA and protein levels are regulated by distinct mechanisms. These involve control at the level of both synthesis and stability and are discussed in Wang et al 25 Consistent with our findings in bladder cancer cell lines, quantitative PCR analysis of 28 primary bladder cancer tissue samples also revealed that CXCR4 was the only chemokine receptor whose mRNA expression levels correlated with tumor stage. High mRNA levels of CXCR4 were seen in invasive and locally advanced bladder cancer (pT2-pT4).…”

Section: Discussionsupporting

confidence: 91%

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

Retz

Sidhu

Blaveri

et al. 2004

Intl Journal of Cancer

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Transitional cell carcinoma of the urinary bladder remains life threatening due to the high occurrence of metastases. Emerging evidence suggests that chemokines and their receptors play a critical role in tumor metastases. In our study, we performed a systematic analysis of the mRNA and protein expression levels of all 18 chemokine receptors in normal urothelium and bladder cancer. CXCR4 was the only chemokine receptor whose mRNA expression level was upregulated in bladder cancer cell lines as well as in invasive and locally advanced bladder cancer tissue samples (pT2-pT4). In contrast, superficial bladder tumors (pTa and pT1) displayed low CXCR4 expression levels and normal urothelial cells were negative for CXCR4. Immunohistochemistry of a bladder cancer tissue microarray (TMA) confirmed that a subgroup of invasive bladder cancers revealed a high CXCR4 protein expression, while superficial bladder tumors showed low immunoreactivity. To investigate the functional significance of CXCR4 expression, we performed migration and invasion assays. Exposure of CXCR4-positive bladder cancer cells to CXCL12 in a Boyden chamber type assay provoked a significant increase in migration as well as invasion across a Matrigel barrier. Enhanced migration and invasion were inhibited by a CXCR4-specific blocking antibody. In contrast, normal urothelial cells did not respond to CXCL12 and lacked chemotactic migration. In conclusion, bladder cancer cells express CXCR4 progressively with advanced tumorigenesis and this receptor interacts with CXCL12 to mediate tumor chemotaxis and invasion through connective tissue. These properties identify CXCR4 as a potential target for the attenuation of bladder cancer metastases. © 2004 Wiley-Liss, Inc.Key words: chemokine; bladder cancer; metastasis; migration; invasion Transitional cell carcinoma of the bladder is the most frequent tumor of the urinary tract. Despite advances in early detection and therapy, bladder cancer remains life threatening due to the high occurrence of metastases. Radical cystectomy is the preferred treatment for muscle-invasive bladder cancer in the United States, Japan and some countries of Europe. However, at least 50% of patients with locally advanced disease are expected to develop systemic progression within 3 years. 1 Patients suffering from metastatic bladder cancer are commonly treated with systemic chemotherapy. Analyzing survival rates from standard chemotherapy schedules such as M-VAC (methotrexate, vinblastine, adriamycin and cisplatin), results are more or less discouraging. In the Loehrer trial, only 5 of 133 (3.7%) of the patients randomized to M-VAC were alive at the 6-year follow-up time. These results indicate that patients with systemic metastases continue to be incurable by chemotherapy. 2,3 Despite the fact that it is the metastases rather than the primary tumors that cause most cancer deaths, there has been little progress in identifying drugs to specifically block metastases.Metastasis is not a simple phenomenon, but a highly organized process com...

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Section: Discussionsupporting

confidence: 91%

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

Retz

Sidhu

Blaveri

et al. 2004

Intl Journal of Cancer

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“…Indeed, human Nos1 is distributed over 160 kb among 29 exons and 28 introns, with nine recognized splice variants in the neuronal tissue cluster (Nos1a-i) regulated by alternate promoter usage in the 5' untranslated region flanking the first exon (Wang et al, 1999;Xie et al, 1995). Of these, Nos1f and Nos1g are predominantly expressed in brain (Wang et al, 1999). Although similar in both size and organization, mouse Nos1 has been much less studied than the human gene and far less is known regarding regulation of inducible expression of different splice variants.…”

Section: Discussionmentioning

confidence: 99%

Nuclear factor kappa-B mediates selective induction of neuronal nitric oxide synthase in astrocytes during low-level inflammatory stimulation with MPTP

2008

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Recent advances in understanding the progression of Parkinson's disease (PD) implicate perturbations in astrocyte function and induction of constitutively expressed neuronal nitric oxide synthase (NOS1) in both human PD and in the MPTP model of the disease. Transcriptional regulation of NOS1 is complex but recent data suggest that nuclear factor kappa B (NF-κB) is an important transcription factor involved in inducible expression of the gene. The data presented here demonstrate that mild activation of primary astrocytes with low or 'sub-optimal' concentrations of MPTP (1 µM) and the inflammatory cytokines tumor necrosis factor alpha (10 pg/ml) and interferon gamma (1 ng/ ml) results in selective induction of Nos1 mRNA and protein, increased production of nitric oxide (NO), and a significant elevation in global protein nitration. This mild inflammatory stimulus also resulted in activation and recruitment of p65 to a putative NF-κB response element located in the Nos1 promoter region flanking exon 1. A role for NF-κB in MPTP-dependent induction of NOS1 was confirmed through overexpression of a mutant IκBα super repressor of NF-κB that prevented induction of NOS1. The data presented here thus demonstrate a role for NF-κB in selective induction of NOS1 during early inflammatory activation of astrocytes stimulated by low-dose MPTP and inflammatory cytokines.

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“…12 At least nine unique exon 1 variants from the upstream region are used to initiate transcription in a tissue/cell-specific manner through usage of alternative promoters. 13 Interestingly, those exon 1 variants enriched in neuronal tissues are clustered in one genomic region whereas those enriched in skeletal muscle are grouped together in another genomic region 75 kb upstream, 13 indicating distinct transcriptional regulatory mechanisms. In addition, it is possible that the human nNOS gene also contains an exon 2 promoter that is analogous to the novel, calciumresponsive exon 2 promoter recently characterized in the rodent.…”

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confidence: 99%

An Alternative Promoter of the Human Neuronal Nitric Oxide Synthase Gene Is Expressed Specifically in Leydig Cells

Wang¹,

Newton²,

Miller³

et al. 2002

The American Journal of Pathology

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Neuronal nitric oxide synthase (nNOS) plays a modulatory role in the biology of a variety of neuroendocrine tissues and is especially relevant to gonadal function. We have previously reported the cloning and characterization of a variant of the nNOS protein, termed testis nNOS (TnNOS), the mRNA for which was restricted in expression to male gonadal tissues. To examine the cell-specificity of the testis-specific NOS regulatory regions we defined patterns of ␤-galactosidase expression of an insertional transgene in which the reporter gene lacZ was under the transcriptional control of the human TnNOS promoter. ␤-galactosidase activity was detected exclusively in the interstitial cells of the testis in transgenic mice. These cells also evidenced positive staining for nNOS protein and were identified as androgen-producing Leydig cells by staining with the Leydig cell marker, P 450 scc. Expression of the promoter was absent in cells of the seminiferous tubules, specifically germline cells of different stages and Sertoli cells. In contrast to the male gonad, ␤-galactosidase activity was not detected in ovaries of adult female mice. Activity was also not evident in organs known to express full-length nNOS, such as skeletal muscle, kidney, or cerebellum. The same pattern of ␤-galactosidase staining was observed in independent transgenic founders and was distinct from that observed for an endothelial NOS promoter/reporter transgene. In the testis of male adult eNOS promoter-reporter transgenic mice, ␤-galactosidase activity was expressed only in endothelial cells of large-and medium-sized arterial blood vessels. Transcriptional activity of the Of the three known human nitric oxide synthases (NOS) isoforms, the neuronal nitric oxide synthase (nNOS) has unique properties. The nNOS (NOS1) isoform is expressed from a very complex human genomic locus spanning 240 kb at 12q24.2.

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RNA diversity has profound effects on the translation of neuronal nitric oxide synthase

Cited by 173 publications

References 33 publications

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

Nuclear factor kappa-B mediates selective induction of neuronal nitric oxide synthase in astrocytes during low-level inflammatory stimulation with MPTP

An Alternative Promoter of the Human Neuronal Nitric Oxide Synthase Gene Is Expressed Specifically in Leydig Cells

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