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Transcriptional landscapes at the intersection of neuronal apoptosis and substance P-induced survival: exploring pathways and drug targets

View Article: PubMed Central - PubMed

ABSTRACT

A change in the delicate equilibrium between apoptosis and survival regulates the neurons fate during the development of nervous system and its homeostasis in adulthood. Signaling pathways promoting or protecting from apoptosis are activated by multiple signals, including those elicited by neurotrophic factors, and depend upon specific transcriptional programs. To decipher the rescue program induced by substance P (SP) in cerebellar granule neurons, we analyzed their whole-genome expression profiles after induction of apoptosis and treatment with SP. Transcriptional pathways associated with the survival effect of SP included genes encoding for proteins that may act as pharmacological targets. Inhibition of one of these, the Myc pro-oncogene by treatment with 10058-F4, reverted in a dose-dependent manner the rescue effect of SP. In addition to elucidate the transcriptional mechanisms at the intersection of neuronal apoptosis and survival, our systems biology-based perspective paves the way towards an innovative pharmacology based on targets downstream of neurotrophic factor receptors.

No MeSH data available.


Related in: MedlinePlus

Protein kinase A (PKA) signaling pathway. The majority of G-protein coupled receptors (GPCR) are associated with activation of distinctive adenylate cyclases (ACs) to regulate intracellular cAMP levels. When active, AC produces the second messenger cAMP in response to a wide range of signal-transduction pathways. The main target of cAMP is PKA. Some of the major substrates of PKA include GSK3. PKA phosphorylates and inactivates GSK3, preventing neurodegeneration. PKA also phosphorylates the transcription factor CREB, which in turn allows the recruitment of the coactivator CREB-binding protein (CBP). Thus, PKA is important for an increasing number of physiological processes, such as regulation of the cell cycle that involves chromatin condensation and decondensation. Apart from PKA, other direct targets of cAMP include PDE, p70S6K/RPS6KB1 and PLA2. Pathway objects and links are described separately in Supplementary Figure 16.
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fig6: Protein kinase A (PKA) signaling pathway. The majority of G-protein coupled receptors (GPCR) are associated with activation of distinctive adenylate cyclases (ACs) to regulate intracellular cAMP levels. When active, AC produces the second messenger cAMP in response to a wide range of signal-transduction pathways. The main target of cAMP is PKA. Some of the major substrates of PKA include GSK3. PKA phosphorylates and inactivates GSK3, preventing neurodegeneration. PKA also phosphorylates the transcription factor CREB, which in turn allows the recruitment of the coactivator CREB-binding protein (CBP). Thus, PKA is important for an increasing number of physiological processes, such as regulation of the cell cycle that involves chromatin condensation and decondensation. Apart from PKA, other direct targets of cAMP include PDE, p70S6K/RPS6KB1 and PLA2. Pathway objects and links are described separately in Supplementary Figure 16.

Mentions: A total of 95 statistically significant pathways were identified in the context of SRGs (Supplementary Data S9). To reduce redundancy of deregulated pathways and simplify their comprehension, the most significant variations implicated in these pathways were summarized in Figures 2,3,4,5,6,7,8 and Supplementary Figures 9–15.


Transcriptional landscapes at the intersection of neuronal apoptosis and substance P-induced survival: exploring pathways and drug targets
Protein kinase A (PKA) signaling pathway. The majority of G-protein coupled receptors (GPCR) are associated with activation of distinctive adenylate cyclases (ACs) to regulate intracellular cAMP levels. When active, AC produces the second messenger cAMP in response to a wide range of signal-transduction pathways. The main target of cAMP is PKA. Some of the major substrates of PKA include GSK3. PKA phosphorylates and inactivates GSK3, preventing neurodegeneration. PKA also phosphorylates the transcription factor CREB, which in turn allows the recruitment of the coactivator CREB-binding protein (CBP). Thus, PKA is important for an increasing number of physiological processes, such as regulation of the cell cycle that involves chromatin condensation and decondensation. Apart from PKA, other direct targets of cAMP include PDE, p70S6K/RPS6KB1 and PLA2. Pathway objects and links are described separately in Supplementary Figure 16.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979452&req=5

fig6: Protein kinase A (PKA) signaling pathway. The majority of G-protein coupled receptors (GPCR) are associated with activation of distinctive adenylate cyclases (ACs) to regulate intracellular cAMP levels. When active, AC produces the second messenger cAMP in response to a wide range of signal-transduction pathways. The main target of cAMP is PKA. Some of the major substrates of PKA include GSK3. PKA phosphorylates and inactivates GSK3, preventing neurodegeneration. PKA also phosphorylates the transcription factor CREB, which in turn allows the recruitment of the coactivator CREB-binding protein (CBP). Thus, PKA is important for an increasing number of physiological processes, such as regulation of the cell cycle that involves chromatin condensation and decondensation. Apart from PKA, other direct targets of cAMP include PDE, p70S6K/RPS6KB1 and PLA2. Pathway objects and links are described separately in Supplementary Figure 16.
Mentions: A total of 95 statistically significant pathways were identified in the context of SRGs (Supplementary Data S9). To reduce redundancy of deregulated pathways and simplify their comprehension, the most significant variations implicated in these pathways were summarized in Figures 2,3,4,5,6,7,8 and Supplementary Figures 9–15.

View Article: PubMed Central - PubMed

ABSTRACT

A change in the delicate equilibrium between apoptosis and survival regulates the neurons fate during the development of nervous system and its homeostasis in adulthood. Signaling pathways promoting or protecting from apoptosis are activated by multiple signals, including those elicited by neurotrophic factors, and depend upon specific transcriptional programs. To decipher the rescue program induced by substance P (SP) in cerebellar granule neurons, we analyzed their whole-genome expression profiles after induction of apoptosis and treatment with SP. Transcriptional pathways associated with the survival effect of SP included genes encoding for proteins that may act as pharmacological targets. Inhibition of one of these, the Myc pro-oncogene by treatment with 10058-F4, reverted in a dose-dependent manner the rescue effect of SP. In addition to elucidate the transcriptional mechanisms at the intersection of neuronal apoptosis and survival, our systems biology-based perspective paves the way towards an innovative pharmacology based on targets downstream of neurotrophic factor receptors.

No MeSH data available.


Related in: MedlinePlus