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==AR signaling== | ==AR signaling== | ||
AR has two mechanisms of action: the DNA binding-dependent (genomic AR signaling) and the DNA binding independent (non-genomic AR signaling). | AR has two mechanisms of action: the DNA binding-dependent (genomic AR signaling) and the DNA binding independent (non-genomic AR signaling). | ||
'''[[Image:Signaling.jpg]]''' | '''[[Image:Signaling.jpg | thumb]]''' | ||
===DNA-Binding dependent actions of the AR=== | ===DNA-Binding dependent actions of the AR=== | ||
In the absence of ligand, the AR is in the cytoplasm and associated with heat-shock and other chaperone proteins. Testosterone is converted into DHT by 5α-reductase, with higher affinity to bind AR. When DHT binds AR, it displaces heat shock proteins, drives the interaction between the N and C terminal, and binds importin-α to translocate the ligand/AR complex into the nucleus. | In the absence of ligand, the AR is in the cytoplasm and associated with heat-shock and other chaperone proteins. Testosterone is converted into DHT by 5α-reductase, with higher affinity to bind AR. When DHT binds AR, it displaces heat shock proteins, drives the interaction between the N and C terminal, and binds importin-α to translocate the ligand/AR complex into the nucleus. | ||
In the nucleus, the receptor dimerizes and binds to AREs in the promoter regions of target genes. At the promoter, the AR is able to recruit members of the basal transcription machinery in addition to other coregulators to facilitate transcription <ref name="Structure" />. AR activity is not only regulated by ligand binding and DNA binding but also by intramolecular interactions between functional domains, by homodimerization and by interactions with cofactors (4). | In the nucleus, the receptor dimerizes and binds to AREs in the promoter regions of target genes. At the promoter, the AR is able to recruit members of the basal transcription machinery in addition to other coregulators to facilitate transcription <ref name="Structure" />. AR activity is not only regulated by ligand binding and DNA binding but also by intramolecular interactions between functional domains, by homodimerization and by interactions with cofactors (4). | ||
This leads to the initiation of transcription, cell proliferation and survival, and negative feedback to inactivate AR transcription <ref name="Bench to Bedside" />. | This leads to the initiation of transcription, cell proliferation and survival, and negative feedback to inactivate AR transcription <ref name="Bench to Bedside" />. | ||
'''[[Image: | '''[[Image:Translocation.jpg | thumb]]''' | ||
===Non-DNA Binding dependent actions of the AR=== | ===Non-DNA Binding dependent actions of the AR=== | ||
It has been shown that the androgen/AR complex activates 2nd messenger pathways including ERK, Akt and MAPK and that it interferes with several key proteins including forkhead box protein A1 (FOXA1), PI3K and receptor tyrosine kinases, including ERBB2 and ERBB3. These effects occur within seconds to minutes of androgen treatment <ref name="Bench to Bedside" /><ref>PMID: 28301631</ref>. | It has been shown that the androgen/AR complex activates 2nd messenger pathways including ERK, Akt and MAPK and that it interferes with several key proteins including forkhead box protein A1 (FOXA1), PI3K and receptor tyrosine kinases, including ERBB2 and ERBB3. These effects occur within seconds to minutes of androgen treatment <ref name="Bench to Bedside" /><ref>PMID: 28301631</ref>. | ||