MOLECULAR & CELLULAR
NEUROBIOLOGY
Master Course Cognitive Neuroscience - Radboud
University, Nijmegen
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Chapter 2: Cells and within cells |
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The receptors for steroid hormones are transcription factors which regulate gene expression. Steroids are very hydrophobic hormones which can cross the blood-brain barrier and have important actions on the brain. Thus, an understanding of the mechanism of action of steroid hormones is important in considering brain function. As an introduction to the next module on transcription factors as receptors (which will concern primarily receptors for steroids), first a short overview of general principles of gene transcription (see also "Transcription") and intracellular signal transduction pathways will be given , |
A gene has two regions, a regulatory region and a coding region. The coding region is in the 3' end of the gene (so-called downstream). The coding region is transcribed into RNAby the enzyme RNA polymerase II. The RNA produced is called the primary transcript (heteronuclear RNA). It is further enzymatically processed to give rise to the mature messenger RNA (mRNA) which is subsequently translated into protein. |
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In the processing of the primary transcript the introns are cut out and the exons (ex = expression) are spliced together to form the mRNA.In the regulatory region one finds the so-called TATA box and promoter elements where transcription factors (with such names as Transcription Factor IIB etc) bind. These transcription factors, collectively called basal transcription factors, form a binding site for the RNA polymerase. They and the polymerase are sufficient to give a very low level of basal transcription of the gene into RNA. |
Further upstream on the gene are enhancer elements which are the sites for binding of yet more transcription factors (also referred to as activating transcription factors). The transcription factors which bind here are often dimers. The binding of these transcription factors causes the DNA to loop such that the transcription factors contact the RNA polymerase and the basal transcription factors. This complex formation strongly activates the polymerase to produce the primary RNA transcript. |
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![]() In considering the CREB family, we have already discussed tyrosine receptor kinase signaling via the MAP Kinase cascade and CREB. This signaling begins at the membrane with the activation of phospholipase C gamma. In this case activated PLC gamma generates diacyl glycerol (DAG) at the membrane. The DAG then activates PKC. The activated PKC phosphorylates another kinase to start a cascade of kinase activations known as the MAP kinase cascade. This ultimately leads to the phosphorylation of transcription factors in the nucleus, including CREB and another one with the name c-Jun (c for cellular because there is also an ocogene form, v-Jun). c-Jun is not phosphorylated by PKA nor CaM Kinases, thus making this pathway somewhat unique for the growth factors (although it can be activated by receptor mechanisms working through Gq and PLC-beta). So, in conclusion......All the membrane-bound receptors, i.e. ion channel receptors (e.g. NMDA receptor via Ca2+), tyrosine kinase receptors, and G-protein-coupled receptors, have links to the nucleus for the regulation of gene expression. |
Finally, consider the steroid
hormone link to the nucleus..... For steroids the link to the nucleus is more direct, namely the receptors themselves are transcription factors. The steroids, being hydrophobic, has no trouble in crossing the cell membrane to find their intracellular receptors. The receptors can be in the cytosol or in the nucleus (depends on which steroid is under consideration). Binding of the steroid induces dimerization and, if the receptor was cytosolic, it now moves to the nucleus. In the nucleus the activated receptor now binds enhancer elements of genes. This leads to enhanced gene expression. |
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![]() The first gene activated can be a transcription factor. An example is the transcription factor c-fos (c because of "cellular", there is also an oncogene form, "viral", v-fos). c-fos dimerizes with another transcription factor, c-jun, to form a complex which can bind to an enhancer called AP-1. The gene coding for c-fos contains a CRE, the binding site for CREB. Thus, the expression of c-fos can be enhanced by PKA and Ca2+ calmodulin dependent protein kinase (CaCal/PK). Because, in this case, it is the first gene to be activated the c-fos gene is termed an "immediate early gene". The c-fos protein then activates, via the AP-1 site on the late gene, the expression of the late gene. Other signals can act directly on the late gene. In the example illustrated above, the MAP kinase cascade is acting on the late gene by phosphorylating and thus activating transcription factors that can bind to enhancer elements on the late gene (such as c-jun or other transcription factors). Similarly, the receptor for glucocorticoid (a steroid hormone) is a transcription factor which, in the steroid-bound form, binds to the glucocorticoid-responsive element (GRE) to induce gene expression. |
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Next page: Transcription factor receptors | Go back to: G-proteins |
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