Cytoskeletal control of gene expression: depolymerization of microtubules activates NF-kappa B.
Cell shape changes exert specific effects on gene expression. It has been speculated that the cytoskeleton is responsible for converting changes in the cytoarchitecture to effects on gene transcription. However, the signal transduction pathways responsible for cytoskeletal-nuclear communication remained unknown. We now provide evidence that a variety of agents and conditions that depolymerize microtubules activate the sequence-specific transcription factor NF-kappa B and induce NF kappa B-dependent gene expression. These effects are caused by depolymerization of microtubule because they are blocked by the microtubule-stabilizing agent taxol. In nonstimulated cells, the majority of NF-kappa B resides in the cytosplasm as a complex with its inhibitor I kappa B. Upon cell stimulation, NF-kappa B translocates to the nucleus with concomitant degradation of I kappa B. We show that cold-induced depolymerization of microtubules also leads to I kappa B degradation and activation of NF-kappa B. However, the activated factor remains in the cytoplasm and translocates to the nucleus only upon warming to 37 degrees C, thus revealing two distinct steps in NF-kappa B activation. These findings establish a new role for NF-kappa B in sensing changes in the state of the cytoskeleton and converting them to changes in gene activity.
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Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla 92093-0636.
Karin
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D001483:Base Sequence; D003599:Cytoskeleton / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D015739:Nocodazole / Q000494:pharmacology; D015398:Signal Transduction; D051996:Transcription Factor RelA
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D015739:Nocodazole