Posttranscriptional regulation of GAP-43 gene expression in PC12 cells through protein kinase C-dependent stabilization of the mRNA.

Perrone‐Bizzozero, Nora I.; Cansino, Victor V.; Kohn, Douglas T.

doi:10.1083/jcb.120.5.1263

Cited by 146 publications

(105 citation statements)

References 65 publications

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“…p38 has been identified as an essential kinase in Page 20 of 48 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 20 regulating IL-1β-mediated mRNA stabilization in multiple studies [12, 15-17, 41-44, 56], of which several have specifically investigated IL-1β-mediated COX-2 and IL-6 mRNA stabilization. On the other hand, PKC has been implicated in the stabilization of a variety of other mRNAs such as, p21, GAP-43 and IL-1β itself [19,20,22,23]. Importantly, PKC has been convincingly implicated in COX-2 mRNA stabilization in several recent studies [21,31,44,54,68] and, indirectly, in IL-6 mRNA stabilization in one older study [69].…”

Section: Discussionmentioning

confidence: 98%

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IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a β-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-α and IL-1β. We found that IL-1β treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNAstabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1β is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications.

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Section: Discussionmentioning

confidence: 98%

“…Another kinase often associated with mRNA stabilization is protein kinase C (PKC). PKC activation has been implicated in mRNA stabilization of, among others, GAP-43 [19,20], COX-2 [21], IL-1β [22] and p21 [23]. Moreover, PKC and p38 target several RNA-binding proteins that bind 3"UTRs and stabilize or destabilize the mRNA.…”

Section: Page 4 Of 48mentioning

confidence: 99%

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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“…In PC12 cells, which adopt characteristics of sympathetic neurons in response to NGF, this is evidenced by changes in gene expression associated with neurite outgrowth, neurotransmitter synthesis, neurotransmitter receptor expression, and the development of electrical excitability. These changes often reflect alterations in the transcriptional activity of various genes, as well as effects on mRNA stability (41)(42)(43)(44). Consistent with the effect of NGF on neuronal differentiation, our studies show that NGF not only causes an increase in total agrin mRNA but also induces the expression of agrin mRNA splice variants with inserts at the Y and Z sites (agrin y4z8 , agrin y4z11 , and agrin y4z19 ), which are specifically expressed by neurons (7,8,15).…”

Section: Discussionmentioning

confidence: 99%

Selective Regulation of Agrin mRNA Induction and Alternative Splicing in PC12 Cells by Ras-dependent Actions of Nerve Growth Factor

Smith¹,

Fanger²,

O'Connor³

et al. 1997

Journal of Biological Chemistry

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The extracellular matrix protein agrin plays an important role in the formation and maintenance of the neuromuscular junction. However, regulation of agrin gene expression and pre-mRNA splicing, important in determining the biological actions of agrin, is not well understood. To begin to identify mechanisms controlling agrin expression, quantitative polymerase chain reaction techniques were used to analyze the effect of growth factors on the expression of agrin mRNA isoforms in rat pheochromocytoma (PC12) cells. Agrin transcripts in untreated cells lacked inserts in the Y and Z sites (agrin y0z0 ), encoding agrin isoforms with low acetylcholine receptor aggregating activity and a primarily non-neuronal tissue distribution. Transcripts encoding isoforms with high aggregating activity and neuronal tissue distribution (agrin y4z8 , agrin y4z11 , and agrin y4z19 ) were not detected. Treatment of PC12 cells with nerve growth factor (NGF) caused a significant increase in total agrin mRNA. In contrast, exposure to epidermal growth factor had no effect. Analysis of alternative splicing of agrin mRNA revealed that NGF elicited a specific increase in agrin y4 and agrin z8 mRNAs that did not occur in the presence of epidermal growth factor, insulin, dexamethasone, or retinoic acid. Analysis of PC12 sublines stably overexpressing a dominant inhibitory form of p21 Ras indicated that NGF induced changes in levels of agrin mRNA and alternative splicing required Ras activity. The results show that NGF can influence important aspects of neuronal differentiation by regulating alternative splicing. Furthermore, these data provide insight into the mechanisms governing agrin gene expression and suggest that neurotrophic factors may play a role in regulating agrin expression in vivo.

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“…Optical densities of the GAP-43 bands were corrected by those of G3PD. As we have shown previously (Perrone-Bizzozero et al, 1993), the decay of the GAP-43 mRNA follows an exponential function, M o ϭ M t e Ϫ t (in which ϭ ln2/T 1/2 ). The half-life (T 1/2 ) of the various GAP-43 transcripts was calculated from the plot of relative mRNA levels versus time of decay by using linear regression analysis.…”

Section: Mrna Stability Analysismentioning

confidence: 99%

“…In some studies, cultures were treated with various agents, including 12-O-tetradecanoylphorbol-13-acetate (TPA; 160 nM), polymyxin B (2000 U/ml), and nerve growth factor (NGF; 100 ng/ml). Samples containing 15 g of cytosolic RNA were processed for Northern blot analysis as described by Perrone-Bizzozero et al (1993). Blots were probed with labeled cDNAs for GAP-43, ␤-globin (Gorman et al, 1983), or glyceraldehyde-3-phosphate dehydrogenase (G3PD).…”

Section: Mrna Stability Analysismentioning

confidence: 99%

Post-Transcriptional Regulation of the GAP-43 Gene by Specific Sequences in the 3′ Untranslated Region of the mRNA

et al. 1997

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We have shown previously that GAP-43 gene expression during neuronal differentiation is controlled by selective changes in mRNA stability. This process was found to depend on highly conserved sequences in the 3Ј untranslated region (3Ј UTR) of the mRNA. To map the sequences in the GAP-43 3Ј UTR that mediate this post-transcriptional event, we generated specific 3Ј UTR deletion mutants and chimeras with the ␤-globin gene and measured their half-lives in transfected PC12 cells. Our results indicate that there are two distinct instability-conferring elements localized at the 5Ј and 3Ј ends of the GAP-43 3Ј UTR. Of these destabilizing elements, only the one at the 3Ј end is required for the stabilization of the mRNA in response to treatment with the phorbol ester TPA. This 3Ј UTR element consists of highly conserved uridine-rich sequences and contains specific recognition sites for two neural-specific GAP-43 mRNAbinding proteins. Analysis of the levels of mRNA and protein derived from various 3Ј UTR deletion mutants indicated that all mutants were translated effectively and that differences in gene expression in response to TPA were attributable to changes in GAP-43 mRNA stability. In addition, the phorbol ester was found to affect the binding of specific RNA-binding proteins to the 3Ј UTR of the GAP-43 mRNA. Given that, like the GAP-43 mRNA, its degradation machinery and the GAP-43 mRNAbinding proteins are expressed primarily in neural cells, we propose that these factors may be involved in the posttranscriptional regulation of GAP-43 gene expression during neuronal differentiation.

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Posttranscriptional regulation of GAP-43 gene expression in PC12 cells through protein kinase C-dependent stabilization of the mRNA.

Cited by 146 publications

References 65 publications

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Selective Regulation of Agrin mRNA Induction and Alternative Splicing in PC12 Cells by Ras-dependent Actions of Nerve Growth Factor

Post-Transcriptional Regulation of the GAP-43 Gene by Specific Sequences in the 3′ Untranslated Region of the mRNA

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