Differential induction of primary-response (TIS) genes in PC12 pheochromocytoma cells and the unresponsive variant PC12nnr5.

Altin, Joseph G.; Kujubu, Dean A.; Raffioni, Simona; Eveleth, D D; Herschman, H. R.; Bradshaw, Ralph A.

doi:10.1016/s0021-9258(19)67608-8

Cited by 43 publications

(7 citation statements)

References 55 publications

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“…These observations are consistent with the view that PMA effects are, at least in part, also induced through tyrosine phosphorylations probably involving soluble kinases as opposed to membrane-bound enzymes. These findings also support previous reports (Damon et al, 1990;Sigmund et al, 1990;Altin et al, 1991) that induction of immediate early response genes by/~NGF and bFGF requires a signal transduction pathway other than PKC. This alternative pathway also is likely to involve tyrosine kinases and therefore may be susceptible to orthovanadate effects.…”

Section: Discussionsupporting

confidence: 92%

“…10). These observations underscore previous findings (Altin et al, 1991) that the tyrosine phosphorylations arising from individual growth factor receptors must be sufficiently unique to account for the variations seen in the gene responses.…”

Section: Discussionsupporting

confidence: 82%

“…The TIS 8 response to NGF or bFGF stimulation was not significantly changed in PC12 cells in which PKC had been down regulated (1 #M PMA for 24 h) as previously reported (Damon et al, 1990;Sigmund et al, 1990;Altin et al, 1991) (Fig. 11).…”

Section: Effect Of Orthovanadate On the Induction Of Immediate Early Response Genessupporting

confidence: 81%

“…The products of some of these genes, such as TIS 8 and c-fos, have been identified as nuclear proteins which may act as transcriptional activators to mediate growth factor responses (Herschman, 1991). However, the signaling pathways involved in their induction are not fully delineated and may involve more than one pathway (Altin et al, 1991). As shown in Fig.…”

Section: Effect Of Orthovanadate On the Induction Of Immediate Early Response Genesmentioning

confidence: 99%

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Effect of nerve growth factor and fibroblast growth factor on PC12 cells: inhibition by orthovanadate.

Bradshaw

1993

The Journal of Cell Biology

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Abstract. Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, causes increased levels of tyrosine phosphorylation and blocks, at noncytotoxic concentrations, the differentiative response of rat pheochromocytoma (PC12) cells to/3-nerve growth factor (/3NGF) and basic fibroblast growth factor (bFGF) in a reversible manner. It also prevents growth factorinduced neurite proliferation in primed cells and causes the retraction of previously formed neurites, even in the presence of/3NGF or bFGE It is equally effective in blocking neurite proliferation by 8-Br-cAMP. Zinc chloride and ammonium molybdate, two other inhibitors of tyrosine phosphatases, also cause parallel decreases in neurite proliferation. Orthovanadate generally reduces the transcription of immediate early response genes (TIS 8 and c-fos) and secondary response genes (ornithine decarboxylase (ODC), acetylcholinesterase (ACHE) and SCG 10) induced by/3NGF, bFGF, EGF, and PMA, albeit in a variable fashion.There was no observed effect on the kinetics of expression as judged by TIS 8 induction by/3NGF and protein kinase C (PKC) downregulation did not change the levels of inhibition by orthovanadate seen in control cells. Orthovanadate does not affect the production of diacylglycerol induced by/3NGF or bFGE These observations are consistent with the view that growth factor stimulation of differentiation in PC12 cells involves at least one other PKC independent pathway, and that cAMP and PMA (and their active analogs) activate tyrosine kinases (albeit probably secondarily), which are at least partially responsible for their actions. Although the exact site(s) of action of orthovanadate that lead to the inhibition of growth factor-induced neurite proliferation are unknown, the results presented suggest that it prolongs tyrosine phosphorylations by nonreceptor tyrosine kinases that act downstream from the receptor kinases.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 82%

Section: Effect Of Orthovanadate On the Induction Of Immediate Early Response Genessupporting

confidence: 81%

Section: Effect Of Orthovanadate On the Induction Of Immediate Early Response Genesmentioning

confidence: 99%

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Effect of nerve growth factor and fibroblast growth factor on PC12 cells: inhibition by orthovanadate.

Bradshaw

1993

The Journal of Cell Biology

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“…Bradshaw, unpublished observations) and exhibit similar mechanistic responses (phospholipid hydrolysis (Altin, J. G., and R. A. Bradshaw, unpublished observations) and immediate-early response gene induction) (Altin et al ., 1991) . Since the FGF receptor family is more complex, there may be a defect in one or more of these species that would affect the neuronal-like responses but still allow internalization and other general responses to occur.…”

Section: Discussionmentioning

confidence: 89%

Nerve growth factor nonresponsive pheochromocytoma cells: altered internalization results in signaling dysfunction

Eveleth

Bradshaw

1992

The Journal of Cell Biology

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Abstract. Variant rat pheochromocytoma (PC12) cells which fail to respond to nerve growth factor (NGF) (PC12nnr5) (Green, S. H., R. E. Rydel, J. L . Connoly, and L. A. Greene. 1986. J. Cell Biol. 102 :830-843) bind NGF at both high and low affinity sites . Although still undefined at the molecular level, these have been referred to as type I (high) and type II (low) receptors . They are apparently composed of two membrane-bound proteins, p75 and the protooncogene trk, both of which bind NGF, and apparently contribute singularly or in concert to the two observed affinities, and to the promotion of the NGF effects . In native PC12 cells, only the high affinity receptors are apparently capable of mediating internalization and degradation . PC12nnr5 cells also display type I bind-HE rat pheochromocytoma line PC12 (Greene and Tischler, 1976) is a widely used cultured cell system for the study of neurotrophic factor-induced differen tiation . Upon exposure to nerve growth factor (NGF),' for example, PC12 cells cease cell division, extend neurites, and produce the many proteins needed to become functioning neurons (for review see Greene and Tischler, 1982) . These reversible effects are mediated by the binding ofNGF to specific receptors on the plasma membrane which results in the production of a variety of intracellular signals that combine to produce the differentiated phenotype (Altin and Bradshaw, 1992) . An important aspect of these and other NGFresponsive cells is the existence of at least two distinct classes of NGF receptors that are distinguished by their affinity (Sutter et al., 1979;Schecter and Bothwell, 1981;Hosang and Shooter, 1985) . Binding experiments generally reveal a relatively small number of type I (high affinity, Kd ti 0.4 nM) NGF receptors and a larger number of type II (low affinity, Kd ti nM) receptors (Suffer et al., 1979;Schecter and Bothwell, 1981;Bernd and Greene, 1984). These binding constants differ primarily by the apparent of rate and the corresponding receptors are sometimes referred to as "slow" (type I) and "fast" (type II) . The two receptor forms apparently 1. Abbreviations used in this paper: bFGF, basic fibroblast growth factor ; NGF, nerve growth factor; PC12, rat clonal pheochromocytoma cells ; PC12nnr5, NGF nonresponsive variant of PC12 cells.

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NGF induces transient but not sustained activation of ERK in PC12 mutant cells incapable of differentiating

et al. 1998

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Activation of receptor tyrosine kinases stimulates a diverse array of cellular responses such as proliferation and differentiation. The first events in the signal transduction pathways mediated by different receptor tyrosine kinases are similar and include activation of the mitogen-activated protein kinase (MAPK) pathway and the induction of immediate early genes. The precise signaling pathways leading to each of the cellular responses mediated by receptor tyrosine kinases are still unknown, although it has been proposed that sustained activation of the MAPK pathway by receptor tyrosine kinases such as the nerve growth factor (NGF) receptor TrkA is sufficient to induce differentiation in PC12 cells. In the present study we examined the effect of NGF on mutant PC12 cells that were derived spontaneously in our cultures. NGF induced normal activation of immediate early genes in these cells, whereas the activation of some delayed response genes, as well as neurite outgrowth, was impaired. Furthermore, activation of the NGF-induced extracellular signal-regulated kinase (ERK) in these cells was transient, not sustained. These results support the hypothesis that sustained activation of ERK plays an important role in activating the induction of delayed response genes. However, sustained ERK activation is not a mandatory condition for the promotion of all the features of differentiated PC12 cells, as NGF could induce transcription of the delayed response gene, transin, in PC12 mutant cells. Taken together, our results suggest that NGF induces differentiation of PC12 cells via several signaling pathways, an important one of which is the MAPK pathway.

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Differential induction of primary-response (TIS) genes in PC12 pheochromocytoma cells and the unresponsive variant PC12nnr5.

Cited by 43 publications

References 55 publications

Effect of nerve growth factor and fibroblast growth factor on PC12 cells: inhibition by orthovanadate.

Effect of nerve growth factor and fibroblast growth factor on PC12 cells: inhibition by orthovanadate.

Nerve growth factor nonresponsive pheochromocytoma cells: altered internalization results in signaling dysfunction

NGF induces transient but not sustained activation of ERK in PC12 mutant cells incapable of differentiating

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