Transcriptional and Posttranscriptional Control of Tyrosine Hydroxylase Gene Expression During Persistent Stimulation of Pituitary Adenylate Cyclase‐Activating Polypeptide Receptors on PC12 Cells: Regulation by Protein Kinase A‐Dependent and Protein Kinase A‐Independent Pathways

Corbitt, James; Vivekananda, Jeevalatha; Wang, Shou Shu; Strong, Randy

doi:10.1046/j.1471-4159.1998.71020478.x

Cited by 40 publications

(24 citation statements)

References 51 publications

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“…The PC12 cell line has been widely used to investigate the various effects of PACAP on neuronal differentiation including neuritogenesis (Deutsch and Sun, 1992;Lazarovici et al, 1998), inhibition of cell division (Deutsch and Sun, 1992), stimulation of expression of neuroendocrine-specific genes such as neuropeptide Y and tyrosine hydroxylase (Corbitt et al, 1998) and changes in electrical excitability and secretion Fig. 9.…”

Section: Discussionmentioning

confidence: 99%

A cAMP-Dependent, Protein Kinase A-Independent Signaling Pathway Mediating Neuritogenesis through Egr1 in PC12 Cells

Ravni¹,

Vaudry²,

Gerdin³

et al. 2008

Molecular Pharmacology

128

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The neurotrophic peptide PACAP (pituitary adenylate cyclaseactivating polypeptide) elevates cAMP in PC12 cells. Forskolin and dibutyryl cAMP mimic PACAP's neuritogenic and cell morphological effects, suggesting that they are driven by cAMP. Comparison of microarray expression profiles after exposure of PC12 cells to either forskolin, dibutyryl cAMP, or PACAP revealed a small group of cAMP-dependent target genes. Neuritogenesis induced by all three agents is protein kinase A (PKA)-independent [not blocked by N- [2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89)] and extracellular signal-regulated kinase (ERK)-dependent [blocked by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio) butadiene (U0126)], and therefore cAMP-dependent target genes potentially mediating neuritogenesis were selected for further analysis based on the pharmacological profile of their induction by PACAP (i.e., mimicking that of neuritogenesis). Small interfering RNA (siRNA) targeting one of these genes, Egr1, blocked PACAPinduced neuritogenesis, and siRNA targeting another, Vil2, blocked a component of the cell size increase elicited by PACAP. Neither siRNA blocked PACAP's PKA-dependent antiproliferative effects. PACAP signaling to neuritogenesis was also impaired by dominant-negative Rap1 expression but was not affected by inhibition of protein kinase C (PKC), indicating a G-protein-coupled receptor-mediated differentiation pathway distinct from the one activated by receptor tyrosine kinase ligands such as nerve growth factor (NGF), that involves both Rap1 and PKC. We have thus identified a cAMP-dependent, PKA-independent pathway proceeding through ERK that functions to up-regulate the transcription of two genes, Egr1 and Vil2, required for PACAP-dependent neuritogenesis and increased cell size, respectively. Dominant-negative Rap1 expression impairs both PACAP-induced neuritogenesis and Egr1 activation by PACAP, suggesting that cAMP elevation and ERK activation by PACAP are linked through Rap1.Neurotrophic factors activating receptor tyrosine kinases, such as nerve growth factor (NGF), promote neurite extension through a cAMP-independent signaling pathway involving Ras, PKC, and ERK (Ginty et al., 1991;Vaudry et al., 2002b), although other effects of NGF, such as induction of sodium channel expression, do require cAMP (Ginty et al., 1992;Yao et al., 1998). A significant literature also implicates cAMP in a broad range of neuronal differentiation responses, including neuritogenesis, survival, regeneration, repair, and expression of genes encoding neuron-specific proteins, such as neurotransmitter biosynthetic enzymes, neuropeptides, receptors, and ion channels (Qiu et al., 2002),

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Section: Discussionmentioning

confidence: 99%

A cAMP-Dependent, Protein Kinase A-Independent Signaling Pathway Mediating Neuritogenesis through Egr1 in PC12 Cells

Ravni¹,

Vaudry²,

Gerdin³

et al. 2008

Molecular Pharmacology

128

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“…7). Interestingly, PACAP exerts a persistent post-transcriptional effect on the steady-state levels of tyrosine hydroxylase in PC12 cells (Corbitt et al, 1998).…”

Section: Tight Regulation Of Otp During Hypothalamic Developmentmentioning

confidence: 98%

Specification of hypothalamic neurons by dual regulation of the homeodomain protein Orthopedia

et al. 2007

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In the developing hypothalamus, a variety of neurons are generated adjacent to each other in a highly coordinated, but poorly understood process. A critical question that remains unanswered is how coordinated development of multiple neuronal types is achieved in this relatively narrow anatomical region. We focus on dopaminergic (DA) and oxytocinergic (OT) neurons as a paradigm for development of two prominent hypothalamic cell types. We report that the development of DA and OT-like neurons in the zebrafish is orchestrated by two novel pathways that regulate the expression of the homeodomain-containing protein Orthopedia (Otp), a key determinant of hypothalamic neural differentiation. Genetic analysis showed that the G-protein-coupled receptor PAC1 and the zinc finger-containing transcription factor Fezl act upstream to Otp. In vivo and in vitro experiments demonstrated that Fezl and PAC1 regulate Otp at the transcriptional and the post-transcriptional levels, respectively. Our data reveal a new genetic network controlling the specification of hypothalamic neurons in vertebrates, and places Otp as a critical determinant underlying Fezl-and PAC1-mediated differentiation.

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“…Finally, it has recently been reported that the neuroprotective effect of nicotine on differentiated PC12 cells could involve PACAP expression (Tominaga et al, 2008). Besides its effects on PC12 cell differentiation and survival, PACAP has been shown to stimulate catecholamine secretion, to induce cell excitability, and to enhance the biosynthesis of other neuropeptides in PC12 cells (Corbitt et al, 1998;Grumolato et al, 2003b;Ravni et al, 2006b). The PACAP-evoked increase in TH expression is regulated through both the PKA and PKC pathways (Corbitt et al, 2002).…”

Section: Effects Of Pituitary Adenylate Cyclase-activating Polypepmentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

et al. 2009

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Transcriptional and Posttranscriptional Control of Tyrosine Hydroxylase Gene Expression During Persistent Stimulation of Pituitary Adenylate Cyclase‐Activating Polypeptide Receptors on PC12 Cells: Regulation by Protein Kinase A‐Dependent and Protein Kinase A‐Independent Pathways

Abstract: Abbreviations used: cAMP, cyclic AMP; PACAP, pituitary adenylate cyclase-activating polypeptide; PKA, protein kinase A, the cyclic AMP-dependent protein kinase; PKC, protein kinase C; TH, tyrosine hydroxylase; VIP, vasoactive intestinal polypeptide.

Cited by 40 publications

References 51 publications

A cAMP-Dependent, Protein Kinase A-Independent Signaling Pathway Mediating Neuritogenesis through Egr1 in PC12 Cells

A cAMP-Dependent, Protein Kinase A-Independent Signaling Pathway Mediating Neuritogenesis through Egr1 in PC12 Cells

Specification of hypothalamic neurons by dual regulation of the homeodomain protein Orthopedia

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

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