Activation of the iNOS gene promoter by Brn-3 POU family transcription factors is dependent upon the octamer motif in the promoter

Gay, Robert D.; Dawson, Sally J.; Murphy, William J.; Russell, Steven; Latchman, David S.

doi:10.1016/s0167-4781(98)00234-6

Cited by 20 publications

(11 citation statements)

References 40 publications

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“…One such factor is the octamer (OCT)-binding protein BRN-2, which is expressed by melanoma cells in response to ERK activation and is associated with melanoma proliferation and survival (Goodall et al, 2004). The iNOS promoter contains an OCT binding site and can be activated in vitro by BRN-3, another member of the OCT family (Gay et al, 1998). The ability of BRN-2 to activate the iNOS promoter is not known, but represents a potentially unique intermediary between the MAPK pathway and iNOS in melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma

et al. 2006

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Activating mutations of the genes for NRAS and BRAF, components of the p44/42 mitogen-activated protein kinase (MAPK) pathway, are common findings in melanoma. Recent evidence in several nonmelanoma cell systems supports the regulation of the inducible nitric oxide synthase (iNOS) gene by this pathway. On the basis of our data showing that melanoma iNOS expression predicts shortened patient survival, we formulated the hypothesis that activating mutations of NRAS or BRAF, which lead to constitutive activation of the p44/42 MAPK pathway, drive iNOS expression in human melanoma. In the present study, we have shown that inhibition of melanoma iNOS activity by S-methylisothiourea leads to decreased cell proliferation, confirming the importance of iNOS activity for melanoma cell growth. Regulation of melanoma iNOS expression by the p44/42 MAPK pathway was demonstrated by inhibition of the pathway by U0126, and by BRAF RNA interference. To explore this regulatory pathway in human tissue, 20 melanoma tumors were examined for NRAS and BRAF mutations, immunohistochemical evidence of ERK phosphorylation, and iNOS expression. A significant association was found among these three features. We conclude that in human melanoma, activating mutations of NRAS and BRAF drive constitutive iNOS expression and, implicitly, nitric oxide production, contributing to the poor survival of these patients.

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Section: Discussionmentioning

confidence: 99%

Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma

et al. 2006

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“…However, our findings appear different from other published in vitro studies. Those studies as such have shown that both Brn3a and Brn3b activate an iNOS promoter in BHK-21 fibroblast cells (Gay et al, 1998). However, the two genes exhibit antagonistic effects on the transcriptional regulation of human papilloma virus (HPV) type 16 and 18 E6 and E7 genes in cell lines of cervical origin (Ndisdang et al, 1998) and on in vitro differentiation of ND7 cells (Smith et al, 1997).…”

Section: Functional Equivalency Of Brn3 Factorsmentioning

confidence: 99%

Functional equivalence of Brn3 POU-domain transcription factors in mouse retinal neurogenesis

Ling

Yang

et al. 2005

Development

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POU-domain transcription factors play essential roles in cell proliferation and differentiation. Previous studies have shown that targeted deletion of each of the three POU-domain Brn3 factors in mice leads to the developmental failure and apoptosis of a unique set of sensory neurons in retina, dorsal root ganglia, trigeminal ganglia and inner ear. The specific defects associated with the removal of each Brn3 gene closely reflect their characteristic spatiotemporal expression patterns. Nevertheless, it remains elusive whether Brn3 factors are functionally equivalent and act through a common molecular mechanism to regulate the development and survival of these sensory neurons. By knocking-in Brn3a (Brn3aki)into the Brn3b locus, we showed here that Brn3akiwas expressed in a spatiotemporal manner identical to that of endogenous Brn3b. In addition, Brn3aki functionally restored the normal development and survival of retinal ganglion cells (RGCs) in the absence of Brn3b and fully reinstated the early developmental expression profiles of Brn3b downstream target genes in retina. These results indicate that Brn3 factors are functionally equal and that their unique roles in neurogenesis are determined by the distinctive Brn3 spatiotemporal expression patterns.

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“…Most of these sequences are inactive showing no protein binding. A distal Oct element (D-Oct in Table 1) forms two protein complexes, but their fast migration indicates that they are smaller polypeptides possibly corresponding to smaller members of the POU family such as Pit-1 or Brn, which have been reported to bind the hiNOS promoter [27]. The proximal Oct element (P-Oct), located at -57 to -64 is the only sequence recognized by a complex of nuclear proteins migrating in a similar pattern to that obtained with the consensus Oct probe.…”

Section: Resultsmentioning

confidence: 99%

“…The N terminus sub-domain of the protein (POU specific domain) contacts the ATGC sequence of the Oct element, while the C terminus or POU homeodomain rests in the AAAT site major groove [29]. It has been classified as a proximal activator that usually functions from a position close to the TATA box, typically activating transcription in response to a remote enhancer [27]. However, active Oct sites in upstream enhancers have also been described, such as the one recently identified [12] in the far upstream hiNOS promoter (10 kb).…”

Section: Discussionmentioning

confidence: 99%

Oct-1 cooperates with the TATA binding initiation complex to control rapid transcription of human iNOS

Reveneau

Petrakis

Goldring

et al. 2012

Cell. Mol. Life Sci.

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Expression of the human inducible nitric oxide synthase (hiNOS) is generally undetectable in resting cells, but stimulation by a variety of signals including cytokines induces transcription in most cell types. The tight transcriptional regulation of the enzyme is a complex mechanism many aspects of which remain unknown. Here, we describe an octamer (Oct) element in hiNOS proximal promoter, located close to the TATA box. This site constitutively binds Oct-1 and its deletion abrogates cytokine-induced transcription, showing that it is indispensable though not sufficient for transcription. Increasing the distance between Oct and the TATA box by inserting inert DNA sequence inhibits transcription, and footprinting of this region shows no other protein binding in resting cells, suggesting an interaction between the two complexes. Chromatin immunoprecipitation assays detect the presence of Oct-1, RNA polymerase II and trimethyl K4 histone H3 on the proximal promoter in resting cells, confirming that the gene is primed for transcription before stimulation. RT-PCR of various fragments along the hiNOS gene shows that transcription is initiated in resting cells and this is inhibited by interference with Oct-1 binding to the proximal site of the promoter. We propose that, through interaction with the initiation complex, Oct-1 regulates hiNOS transcription by priming the gene for the rapid response required in an immune response.

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Activation of the iNOS gene promoter by Brn-3 POU family transcription factors is dependent upon the octamer motif in the promoter

Cited by 20 publications

References 40 publications

Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma

Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma

Functional equivalence of Brn3 POU-domain transcription factors in mouse retinal neurogenesis

Oct-1 cooperates with the TATA binding initiation complex to control rapid transcription of human iNOS

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