Nuclear proteasomal degradation and cytoplasmic retention underlie early nuclear exclusion of transcription factor Max upon axon damage.
The behavior of the transcription factor Max in axon-damaged retinal ganglion cells (RGC) was investigated in explants from the rat retina, used as a tissue culture model of the central nervous system (CNS). Axon damage leads to an apparent rapid shift in the localization of Max from the nucleus to the cytoplasm, in advance of markers of apoptosis. This nuclear exclusion resisted treatments with calpeptin or the CRM1 exportin inhibitor leptomycin B, but was prevented by low temperature. Inhibition of either transcription or translation prevented RGC death, but only the latter robustly prevented nuclear exclusion. The proteasome inhibitor lactacystin prevented nuclear exclusion, whereas newly synthesized Max still accumulated in the cytoplasm of the axon-damaged RGC. The results show that proteosomal degradation of nuclear Max coupled with continued expression and cytoplasmic accumulation of Max, with blockade of nucleocytoplasmic transport of the newly synthesized protein, is an early event after CNS axonal damage.
Petrs-Silva
Hilda
H
Instituto de Biofisica da UFRJ, CCS, bloco G, Cidade Universitaria, 21941-900, Rio de Janeiro, Brazil.
Chiarini
Luciana B
LB
Linden
Rafael
R
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009924:Organ Culture Techniques; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014855:Wallerian Degeneration / Q000378:metabolism* / Q000503:physiopathology; D000097606:Exportin 1 Protein
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004151:Dipeptides; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D046988:Proteasome Endopeptidase Complex; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C499329:Max protein, rat; C071482:calpeptin; C038753:leptomycin B