DGIF 2018

Abstract :

The aging dependent cellular behaviors toward extrinsic stress are characterized by the confined localization of the certain molecules either to nuclear or perinuclear regions. Most of the growth factors can activate the downstream signals of the aging cells but in vain, since those signals cannot reach the genetic targets in the nuclei. At the same time, varying apoptotic stress factors cannot stimulate the apoptotic pathway of the senescent cells, since those subsequent downstream signals cannot get into nuclei as well. Thereby, operation of the functional nuclear barrier in an aging dependent manner has been issued. In search of the ultimate mechanism for these aging dependent changes of the functional nuclear barrier, the transcription factor Sp1 is identified as a general regulator for nucleocytoplasmic trafficking (NCT) genes, including various nucleoporins, importins, exportins and Ran GTPase cycle-related genes, through serial experiments with knockdown and overexpression of the related genes. Sp1 is essentially one of the housekeeping genes, but its protein status is readily influenced by the extrinsic stress, either oxidative or metabolic stress. Its decreased O-GlcNAcylation both in senescent cells and in H₂O₂ treated cells sensitizes its proteosomal degradation, resulting in the defective NCT functions, leading to nuclear barrier formation. This novel mechanism of aging dependent operation of the functional nuclear barrier is proposed as the ultimate checking mechanism for cellular protection against toxic environment and the general mechanism for tradeoff growth to survival in aging.