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Calcium and proto-oncogene involvement in the immediate-early response in the nervous system
1Department of Neuroscience, Roche Institute of Molecular Biology, Nutley, New Jersey 07110.
Abstract:
Depolarization of neurons either in culture or in vivo results in the rapid, calcium-dependent induction of several, so-called, immediate-early genes; the prototypes being c-fos and c-jun. The proteins encoded by c-jun, c-fos, and several fos-related genes all participate in a complex that interacts with the AP-1 consensus DNA sequence, previously shown to be important for the "transcriptional activation" of certain genes. Thus it is proposed that neuronal stimulation, via elevated intracellular calcium, leads to the induction of a series of genes, some of which encode proteins involved in transcriptional regulation, that contribute to long-term adaptive and plastic responses. Surprisingly, the molecular composition of the brain AP-1 binding complex varies with time after stimulation. This is because some of the inducible Fos-related proteins accumulate with much slower kinetics than Fos itself and only appear in significant amounts when Fos has disappeared. Of some considerable interest is the result these compositional alterations have upon the transcriptional activity of the AP-1 complex. Given the foregoing findings we consider some of the possible implications this might have for aging and neurodegenerative disorders particularly with regard to alterations in cellular calcium homeostasis.
Insights
Neuronal stimulation rapidly activates immediate-early genes like c-fos and c-jun, influencing brain plasticity. The composition of the AP-1 complex changes over time, impacting gene regulation and potentially neurodegenerative disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Neuronal depolarization triggers immediate-early gene expression, including c-fos and c-jun.
- These genes encode proteins that form a complex interacting with the AP-1 DNA sequence, crucial for transcriptional activation.
- This process is calcium-dependent and linked to neuronal adaptation and plasticity.
Purpose of the Study:
- To investigate the dynamic changes in the AP-1 binding complex composition following neuronal stimulation.
- To explore how alterations in the AP-1 complex affect transcriptional activity over time.
- To consider the implications of these molecular changes for aging and neurodegenerative diseases, particularly concerning calcium homeostasis.
Main Methods:
- Utilized cell cultures and in vivo models of neuronal depolarization.
- Analyzed the induction of immediate-early genes (c-fos, c-jun) and related proteins.
- Examined the molecular composition and DNA-binding activity of the AP-1 complex at different time points post-stimulation.
Main Results:
- Neuronal stimulation rapidly induced c-fos and c-jun gene expression.
- The molecular composition of the AP-1 binding complex was found to vary dynamically over time after stimulation.
- Slower-accumulating Fos-related proteins altered the AP-1 complex's transcriptional activity as Fos levels declined.
Conclusions:
- Neuronal stimulation leads to calcium-dependent gene induction, involving transcription factors that regulate adaptive brain responses.
- Temporal changes in AP-1 complex composition significantly influence gene transcription.
- These findings suggest potential links between altered calcium homeostasis, dynamic AP-1 complex activity, and neurodegenerative disorders.