Tranduction Regulation of Transcription

Phosphorylated beta catenin targeted to proteosome

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Phosphorylated beta-catenin targeted to proteosome for destruction TCF transcription factor binds to response element in target genes and keeps them turned off Wnt signaling: OFF 23
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+ ligand Activated receptor sequesters Axin to plasma membrane Disrupts interaction with APC and GSK3 Beta-catenin no longer phosphorylated--> no longer destroyed Beta-catenin translocates into nucleus Beta-catenin binds to TCF and activates target genes Wnt signaling: ON 24
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25 Hedgehog Signaling Players Receptors - Patched (12 TM spanning) Smoothened (7 TM spanning) Ligands- Hedgehogs (lipid-modified) Intracellular Effectors - Positive Regulators: Cubitus Interruptus (full length TF) Negative Regulators: Costal (kinesin-like protein) Fused kinase Slimb Cubitus Interruptus (short TF) Cyclopic sheep Corn flower containing cyclopamine
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No ligand Patched membrane protein inhibits Smoothened Transcription Factor Cubitus interruptus (Ci) interacts with Costal and Fused in cytoplasm Ci is phosphorylated which targets it for proteosomal cleavage via Slimb Short Ci translocates into nucleus and binds to Hh target genes Short Ci represses the transcription of target genes Hedgehog signaling: OFF 26
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+ ligand Hh binding inhibits Patched Binding releases inhibition on Smoothened Smoothened at the plasma membrane recruits Costal and Fused to membrane Ci no longer associates with inhibitor proteins Ci is no longer cleaved Full length Ci translocates into nucleus and binds to Hh target genes Full length Ci activates the transcription of target genes Hedgehog signaling: ON 27
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Signs of Pathway Activation: Extended Version Detection of second messenger levels cAMP Ca++ IP3 DAG Phosphorylation of targets/Kinase activity PKA activity TGF-beta Type II activity Smad phosphorylation Transcription of target genes/Transcription Factor activity RT-PCR for target gene levels Promoter-driven reporter assays Levels of cleaved/degraded effector proteins Beta-catenin Cubitus interruptus Localization of nuclear translocated effectors Smads MAPK Beta-catenin 28
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