Influence of Ras and retinoic acid on nerve growth factor induction of transin gene expression in PC12 cells

Cosgaya, José Miguel; Recio, Juan A.; Aranda, Ana

doi:10.1038/sj.onc.1200997

Cited by 10 publications

(13 citation statements)

References 26 publications

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“…6, incubation with the glucocorticoid, which strongly increased RARβ2 promoter activity, caused a much weaker activation of the DR5‐TK construct. Furthermore, the activity of the RSV promoter which, in agreement with previous results from our laboratory, was specifically induced by Ras Val12 (Cosgaya et al . 1997a) was unaffected by RA.…”

Section: Resultssupporting

confidence: 91%

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Nerve growth factor activates the RARβ2 promoter by a Ras‐dependent mechanism

Cosgaya

Aranda

2001

Journal of Neurochemistry

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Nerve growth factor (NGF) and retinoic acid (RA) exert important actions on PC12 cells. We have previously shown that incubation with NGF induces retinoic acid receptor b (RARb) binding to a hormone response element in PC12 cells. In this study we show that NGF increases RARb protein levels by enhancing basal RARb2 promoter activity, and potentiates stimulation by RA in transient transfection assays. The effect of RA is mediated by a RA response element (RARE) located at 237/253 and mutation of this element abolishes activation by the retinoid, as well as cooperation with NGF. However, the action of NGF is independent of the RARE and is mediated by sequences overlapping the TATA box and the INR comprising nucleotides 259 to 114. NGF produces a strong decrease in some of the complexes that bind to the INR. These results suggest that the RARb 2 gene could be in a basal repressed state and NGF could increase RARb2 transcription by inducing the release of some inhibitory factors from the INR. Functional Ras is required for RARb2 promoter activation by NGF because expression of oncogenic Ras increases promoter activity and a dominant inhibitory Ras mutant blocks the effect of NGF. Oncogenic Raf also mimics the effect of NGF on the promoter. Other ligands of tyrosine kinase receptors that stimulate Ras also cause RARb2 promoter activation and act cooperatively with RA. These results indicate the existence of cross-coupling of the Ras±Raf signal transduction pathway with retinoid receptor pathways which could increase sensitivity to RA and be important for PC12 cell function.

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Section: Resultssupporting

confidence: 91%

“…1996). In addition, RA causes a transient expression of the low affinity neurotrophin receptor p75 NTR , tyrosine hydroxilase and TGF‐β1 genes similar to that observed during NGF‐induced differentiation (Cosgaya and Aranda 1996; Cosgaya et al . 1997b).…”

Section: Discussionmentioning

confidence: 62%

Nerve growth factor activates the RARβ2 promoter by a Ras‐dependent mechanism

Cosgaya

Aranda

2001

Journal of Neurochemistry

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“…RA-induced neuronal differentiation is characterized by the expression of tissue-specific genes, proteins, ion channels, and receptors in a developmentally controlled manner (Guan et al, 2001). Although we have previously shown that RA inhibits PC12 cell proliferation and mimics the effect of neurotrophins on the expression of several genes, the retinoid does not cause neurite extension and does not increase the levels of early response genes such as c-fos in parental PC12 cells (Cosgaya et al, 1996(Cosgaya et al, , 1997a(Cosgaya et al, , 1997b(Cosgaya et al, , 1998. In contrast, RA can stimulate the differentiation of some PC12 cell subclones.…”

Section: Introductionmentioning

confidence: 83%

“…Cell 10.1091/ mbc.E04 -05-0439. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E04 -05-0439. c-fos in parental PC12 cells (Cosgaya et al, 1996(Cosgaya et al, , 1997a(Cosgaya et al, , 1997b(Cosgaya et al, , 1998. In contrast, RA can stimulate the differentiation of some PC12 cell subclones.…”

Section: Introductionmentioning

confidence: 99%

Rapid Effects of Retinoic Acid on CREB and ERK Phosphorylation in Neuronal Cells

Cañón

Cosgaya

Scsucova

et al. 2004

MBoC

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160

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Retinoic acid (RA) is a potent regulator of neuronal cell differentiation. RA normally activates gene expression by binding to nuclear receptors that interact with response elements (RAREs) in regulatory regions of target genes. We show here that in PC12 cell subclones in which the retinoid causes neurite extension, RA induces a rapid and sustained phosphorylation of CREB (cyclic AMP response element binding protein), compatible with a nongenomic effect. RA also causes a rapid increase of CREB phosphorylation in primary cultures of cerebrocortical cells and of dorsal root ganglia neurons from rat embryos. RA-mediated phosphorylation of CREB leads to a direct stimulation of CREB-dependent transcriptional activity and to activation of the expression of genes such as c-fos, which do not contain RAREs but contain cAMP response elements (CREs) in their promoters. CREB is a major target of extracellular signal regulated kinase ERK1/2 signaling in neuronal cells, and we demonstrate here that RA induces an early stimulation of ERK1/2, which is required both for CREB phosphorylation and transcriptional activity. These results demonstrate that RA, by a nongenomic mechanism, stimulates signaling pathways that lead to phosphorylation of transcription factors, which in turn activate the transcription of genes involved in neuronal differentiation. INTRODUCTIONPC12 cells, cloned from a rat pheochromocytoma have been widely used for studying molecular mechanisms of neuronal differentiation. On incubation with neurotrophic factors such as nerve growth factor (NGF) these cells extend long neurites and undergo biochemical changes characteristic of mature sympathetic neurons (Segal and Greenberg, 1996). The neuron-like differentiation of PC12 cells induced by NGF involves activation of the Ras/extracellular signal-regulated kinase (ERK1/2) signaling pathway. Sustained activation of ERK1/2 permits its translocation to the nucleus, where it may modulate gene expression via the phosphorylation of transcription factors or activation of other kinases (Qiu and Green, 1991;Marshall, 1995).The nuclear transcription factor cAMP response elementbinding protein (CREB) is a major downstream target of ERK1/2 signaling that contributes to neuronal differentiation in PC12 cells (Heasley et al., 1991;Ginty et al., 1994) and to brain neuroplasticity (Impey et al., 1998bSgambato et al., 1998;Pham et al., 1999) and neuronal survival (Bonni et al., 1999;Riccio et al., 1999;Nakagawa et al., 2002). CREB binds constitutively to the specific DNA motif, 5Ј-TGACGTCA-3Ј known as CRE, and its activity is triggered by phosphorylation in Ser133 (González and Montminy, 1989). Phosphorylation of Ser133 recruits the CREB binding protein, CBP, to the initiator complex and thereby promotes transcription (Chrivia et al., 1993;Arias et al., 1994;Mayr and Montminy, 2001). CREB was initially identified as a substrate for PKA and as a mediator of cAMP-regulated gene expression, but later studies showed that CREB can be phosphorylated and activated by multiple signaling p...

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“…Because microarray analysis may miss changes in gene expression when genes are expressed at low levels, we asked whether genes that are involved in cell adhesion and that are regulated by Ras and oncogenic ETS factors were repressed by TEL (73). MMPs are stimulated by Ras through the activation of ETS and AP-1 factors and repressed by negatively acting ETS factors such as Erg (15,16,29,33,59,80). RNA blot analysis indicated that the levels of the MMPs expressed in NIH 3T3 cells, including MMP1, MMP7, and MMP9, were low in these cells and were not affected by TEL (data not shown).…”

Section: Resultsmentioning

confidence: 99%

TEL, a Putative Tumor Suppressor, Modulates Cell Growth and Cell Morphology of Ras-Transformed Cells While Repressing the Transcription of stromelysin-1

Fenrick

Wang

Nip

et al. 2000

Molecular and Cellular Biology

135

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TEL is a member of the ETS family of transcription factors that interacts with the mSin3 and SMRT corepressors to regulate transcription. TEL is biallelically disrupted in acute leukemia, and loss of heterozygosity at the TEL locus has been observed in various cancers. Here we show that expression of TEL in Ras-transformed NIH 3T3 cells inhibits cell growth in soft agar and in normal cultures. Unexpectedly, cells expressing both Ras and TEL grew as aggregates. To begin to explain the morphology of Ras-plus TELexpressing cells, we demonstrated that the endogenous matrix metalloproteinase stromelysin-1 was repressed by TEL. TEL bound sequences in the stromelysin-1 promoter and repressed the promoter in transient-expression assays, suggesting that it is a direct target for TEL-mediated regulation. Mutants of TEL that removed a binding site for the mSin3A corepressor but retained the ETS domain failed to repress stromelysin-1. When BB-94, a matrix metalloproteinase inhibitor, was added to the culture medium of Ras-expressing cells, it caused a cell aggregation phenotype similar to that caused by TEL expression. In addition, TEL inhibited the invasiveness of Ras-transformed cells in vitro and in vivo. Our results suggest that TEL acts as a tumor suppressor, in part, by transcriptional repression of stromelysin-1.The TEL (for "translocation-ETS-leukemia," also referred to as ETV6) transcription factor is a target for disruption by chromosomal translocations in several forms of acute leukemia (24-27, 38, 50, 51, 54, 57, 63). TEL was originally identified as the gene on chromosome 12 that is disrupted by t(5;12) in patients with chronic myelomonocytic leukemia (25). This translocation fuses the N-terminal homodimerization domain of TEL to the tyrosine kinase domain of the platelet-derived growth factor receptor ␤. The N terminus of TEL is also fused to the majority of the AML-1B (Runx-1) transcription factor by t(12;21), which is the most frequent translocation in pediatric B-cell acute lymphoblastic leukemias (23,26,57,61).TEL is a member of the ETS family of transcription factors. ETS factors bind heterogenous sequences centered around a core GGA sequence and cooperate with other transcription factors to regulate the transcription of a diverse set of genes (28,52,74). Several ETS factors are downstream effectors of oncogenic Ras proteins and are phosphorylated by mitogenactivated protein kinases (73,80). Aberrant expression of these ETS factors induces cellular transformation (73, 74). By contrast, TEL acts as a transcriptional repressor. In t(12;21),

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Influence of Ras and retinoic acid on nerve growth factor induction of transin gene expression in PC12 cells

Cited by 10 publications

References 26 publications

Nerve growth factor activates the RARβ2 promoter by a Ras‐dependent mechanism

Nerve growth factor activates the RARβ2 promoter by a Ras‐dependent mechanism

Rapid Effects of Retinoic Acid on CREB and ERK Phosphorylation in Neuronal Cells

TEL, a Putative Tumor Suppressor, Modulates Cell Growth and Cell Morphology of Ras-Transformed Cells While Repressing the Transcription of stromelysin-1

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