1/4/2023 0 Comments Crack f4 transcription![]() The advent of high-throughput technologies is now offering a systems biology-based perspective to analyze the mechanisms underlying neuronal apoptosis and survival. 6 Although their effects are mediated by different receptors and intracellular second messengers, their signaling pathways converge into the nucleus and regulate gene expression. 2 Before this ‘commitment point’ CGNs can be rescued by the activation of specific signal-transduction pathways or by the treatment with specific neurotrophic factors, such as insulin-like growth factor-1 (IGF-1), 2 pituitary adenylyl cyclase-activating polypeptide (PACAP), 3, 4 gastric inhibitory polypeptide (GIP) 5 and substance P (SP). Engagement of apoptosis requires transcription and protein synthesis and becomes irreversible after 6 h from induction. 1 In this in vitro paradigm, a rapid apoptotic cell death occurs within 24 h after removal of serum and lowering of extracellular potassium from 25 to 5 mM. Primary cultures of cerebellar granule neurons (CGNs) represent the election model to examine the mechanisms underlying neuronal apoptosis and survival. These programs are activated by multiple extracellular and/or intracellular signals, including the absence or presence of neurotrophic factors. Neuronal apoptosis and survival are orchestrated by intrinsic transcriptional programs regulating. 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. 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. Transcriptional pathways associated with the survival effect of SP included genes encoding for proteins that may act as pharmacological targets. 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. Signaling pathways promoting or protecting from apoptosis are activated by multiple signals, including those elicited by neurotrophic factors, and depend upon specific transcriptional programs. 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. ![]()
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