Neurite Outgrowth and Protein Phosphorylation in Chick Embryonic Sensory Ganglia Induced by a Brief Exposure to 12‐<i>O</i>‐Tetradecanoylphorbol 13‐Acetate

Mehta, Sujata; Hsu, Linda; Jeng, Arco Y.; Chen, Kuang Yu

doi:10.1111/j.1471-4159.1993.tb03244.x

Cited by 9 publications

(2 citation statements)

References 35 publications

(25 reference statements)

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“…Such a mechanism would fit with findings that neurite outgrowth in several systems is associated with phosphorylation of numerous proteins in the neurite extensions (35,36). Protein kinase C-mediated phosphorylation has been implicated in process outgrowth during neuronal regeneration (37)(38)(39)(40)(41). Other evidence suggests inhibitory effects of protein kinase C in neuronal process extension (42)(43)(44)(45).…”

supporting

confidence: 54%

Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia.

Lyons

George

Dawson

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

263

161

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The Immunosuppressant drug FK506 acts by binding to receptor proteins, FK506-binding proteins (FKBPs), which in turn can bind to and regulate a Ca2+-dependent phosphatase, calcineurin, and a Ca2+ release channel, the ryanodine receptor. Based on our fins in regeneration models that levels of FKBPs during neural regeneration parallel those of growth-aociated protein GAP43, a calcineurin substrate that regulates neurite extension, we examid effects of FK506 in PC12 rat pheochromocytoma cells and in rat sensory ganglia. FK506 enhances neurite outgrowth in both systems by increaing sensitivity to nerve growth factor. Blockade of FK506 actions in sensory galka by rapamycin, an FK506 antagonist, establishes that these effects involve FKBPs. Rapamycin itself stimulates neurite outgrowth in PC12 cells. These drug effects are detected at sub omolar concentrations, suggesang therapeutic application in diseases involving neural degeneration.The immunosuppressant drugs cyclosporin A and FK506 are thought to exert their therapeutic effects by binding to receptor proteins designated cyclophilins and FK506-binding proteins (FKBPs) respectively. When complexed to the immunosuppressant drugs, these binding proteins, designated immunophilins, bind to the Ca2+-activated phosphatase calcineurin to inhibit its activity and increase levels of phosphorylated calcineurin substrate proteins (1-9). Concentrations of the immunophilins are far higher in the brain and peripheral nervous system than in immune tissues, and FKBP is colocalized with calcineurin throughout the brain, suggesting an important functional relationship (4). We recently showed that cyclosporin A and FK506 block the neurotoxicity elicited by glutamate acting at N-methyl-Daspartate (NMDA) receptors in cerebral cortical cultures (10). The mechanism for the neuroprotective effects of these drugs appears to be inhibition of calcineurin with an augmentation of phosphorylated levels of nitric oxide synthase (NOS) (10). Since phosphorylation of NOS inhibits its catalytic activity (11), the immunosuppressants effectively reduce NO formation, preventing the neurotoxic effects of NMDA in these cultures (12, 13).GAP43 is a prominent protein in neuronal processes associated with neurite extension and is also a major calcineurin substrate (14). Regeneration of damaged facial and sciatic nerves is associated with a marked augmentation of GAP43 mRNA levels (15)(16)(17)(18) IlTo whom reprint requests should be addressed. 3191The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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supporting

confidence: 54%

Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia.

Lyons

George

Dawson

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

263

161

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“…Phorbol esters induce neural tissue from ectoderm in Xenopus embryos (5) and elicit neurite outgrowth from chick sensory ganglia (6,7), chick ciliary ganglion neurons (8), several human neuroblastoma cell lines (9,10), and rat PC12 cells (11,12). Studies using purified isozymes, kinase-defective mutants, and transgenic or mutant cell lines have implicated PKC␣, -␤, -␦, -⑀, and -in the differentiation of nonneural cells (13)(14)(15)(16)(17).…”

Section: Protein Kinase C (Pkc)mentioning

confidence: 99%

An Inhibitory Fragment Derived from Protein Kinase Cε Prevents Enhancement of Nerve Growth Factor Responses by Ethanol and Phorbol Esters

Hundle

McMahon

Dadgar

et al. 1997

Journal of Biological Chemistry

109

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We have studied nerve growth factor (NGF)-induced differentiation of PC12 cells to identify PKC isozymes important for neuronal differentiation. Previous work showed that tumor-promoting phorbol esters and ethanol enhance NGF-induced mitogen-activated protein (MAP) kinase activation and neurite outgrowth by a PKC-dependent mechanism. Ethanol also increases expression of PKC␦ and PKC⑀, suggesting that one these isozymes regulates responses to NGF. To examine this possibility, we established PC12 cell lines that express a fragment encoding the first variable domain of PKC⑀ (amino acids 2-144), which acts as an isozyme-specific inhibitor of PKC⑀ in cardiac myocytes. Phorbol esterstimulated translocation of PKC⑀ was markedly reduced in these PC12 cell lines. In addition, phorbol ester and ethanol did not enhance NGF-induced MAP kinase activation or neurite outgrowth in these cells. In contrast, phorbol ester and ethanol increased neurite outgrowth and MAP kinase phosphorylation in cells expressing a fragment derived from the first variable domain of PKC␦. These results demonstrate that PKC⑀ mediates enhancement of NGF-induced signaling and neurite outgrowth by phorbol esters and ethanol in PC12 cells. Protein kinase C (PKC)1 is a multigene family of phospholipiddependent, serine-threonine kinases that plays a central role in cell growth and differentiation. Molecular cloning studies have identified 10 isozymes encoded by 9 different mRNAs (1, 2). Based on sequence homology and biochemical properties, the PKC gene family has been divided into three groups: "conventional" PKCs (␣, ␤I, ␤II, and ␥) regulated by calcium and diacylglycerols or phorbol esters; "novel" PKCs (⑀, ␦, , and ), which are calcium-independent but diacylglycerol-and phorbol ester-sensitive; and "atypical" PKCs (, and /), which are insensitive to calcium, diacylglycerol, and PMA. In addition, two related phospholipid-dependent kinases, PKC and protein kinase D, share sequence homology in their regulatory domains to novel PKCs and may constitute a new subgroup (3, 4).Several studies with tumor-promoting phorbol esters suggest that PKC modulates neural differentiation. Phorbol esters induce neural tissue from ectoderm in Xenopus embryos (5) and elicit neurite outgrowth from chick sensory ganglia (6, 7), chick ciliary ganglion neurons (8), several human neuroblastoma cell lines (9, 10), and rat PC12 cells (11, 12). Studies using purified isozymes, kinase-defective mutants, and transgenic or mutant cell lines have implicated PKC␣, -␤, -␦, -⑀, and -in the differentiation of nonneural cells (13-17). Overexpression of PKC␣ or -␤ in Xenopus embryos enhances neural induction (18), but little else is known about the identity of specific PKC isozymes that regulate neural differentiation.Recent evidence suggests that PKC⑀ plays a role in neural differentiation and plasticity. PKC⑀ is expressed predominantly in the nervous system and is particularly abundant in the hippocampus, olfactory tubercle, and layers I and II of cerebral cortex (19). Within immunoreactiv...

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Nerve growth factor-induced differentiation of PC12 cells employs the PMA-insensitive protein kinase C-ζ isoform

Coleman

Wooten

1994

J Mol Neurosci

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To elucidate the role of protein kinase C (PKC) in nerve growth factor (NGF)-induced differentiation, PMA downregulation of pheochromocytoma (PC12) cells was undertaken. Prolonged treatment (2 d) of PC12 cells with PMA (1 microM) resulted in depleting the cells of alpha, beta, delta, and epsilon-PKC isoforms, but had no effect on the expression of the atypical PKC isoform zeta. PC12 cells, which expressed only PKC zeta, were evaluated for their responses to NGF. Removal of the PMA-sensitive PKC isoforms enhanced the ability of NGF to promote neurite extension. Both the percentage cells with neurites and length of neurites were increased in the PMA-treated cells, whereas no effect was observed on the number of neurites per cell or branching of individual neurites. In addition, PMA downregulation resulted in an increase in the incorporation of 3H-thymidine without any significant effect on the expression of c-fos. Addition of NGF to PC12 cells depleted of the PMA-sensitive PKC isoforms resulted in the activation of PKC zeta (Wooten et al., 1994). To test whether the transient activation of PKC zeta is a necessary component of the neuritogenetic pathway, antisense oligonucleotide strategy was utilized to remove this particular PKC isoform. The addition of a 20-bp antisense oligonucleotide directed against the 5' coding sequence of PKC zeta attenuated NGF-induced neurite outgrowth in PC12 cells lacking PMA-sensitive PKC isoforms. Sense oligonucleotide directed at the same site was without effect on NGF responses. These data indicate that PKC zeta comprises a portion of the NGF pathway and underscores the importance of this isoform in neuronal differentiation. Moreover, these findings demonstrate that the PMA-insensitive pathway, which was previously characterized as PKC-independent, and the neurite induction pathway are synonymous and mediated by PKC zeta.

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Neurite Outgrowth and Protein Phosphorylation in Chick Embryonic Sensory Ganglia Induced by a Brief Exposure to 12‐O‐Tetradecanoylphorbol 13‐Acetate

Cited by 9 publications

References 35 publications

Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia.

Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia.

An Inhibitory Fragment Derived from Protein Kinase Cε Prevents Enhancement of Nerve Growth Factor Responses by Ethanol and Phorbol Esters

Nerve growth factor-induced differentiation of PC12 cells employs the PMA-insensitive protein kinase C-ζ isoform

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