An elevated frequency of DNA replication defects is associated with diabetes and cancer. However, data linking these nuclear perturbations to the onset or progression of organ complications remained unexplored. Here, we report that RAGE (Receptor for Advanced Glycated Endproducts), previously believed to be an extracellular receptor, upon metabolic stress localizes to the damaged forks. There it interacts and stabilizes the minichromosome-maintenance (Mcm2-7) complex. Accordingly, RAGE deficiency leads to slowed fork progression, premature fork collapse, hypersensitivity to replication stress agents and reduction of viability, which was reversed by the reconstitution of RAGE. This was marked by the 53BP1/OPT-domain expression and the presence of micronuclei, premature loss-of-ciliated zones, increased incidences of tubular-karyomegaly, and finally, interstitial fibrosis. More importantly, the RAGE-Mcm2 axis was selectively compromised in cells expressing micronuclei in human biopsies and mouse models of diabetic nephropathy and cancer. Thus, the functional RAGE-Mcm2/7 axis is critical in handling replication stress in vitro and human disease.

• MeSH
• diabetes mellitus * MeSH
• lidé MeSH
• MCM komplex, komponenta 2 genetika   MeSH
• MCM proteiny metabolismus   MeSH
• myši MeSH
• nádory * MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• replikace DNA genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In mammalian cells inhibition of the cdc2 function results in arrest in the G2-phase of the cell cycle. Several cdc2-related gene products have been identified recently and it has been hypothesized that they control earlier cell cycle events. Here we have studied the relationship between activation of one of these cdc2 homologs, the cdk2 protein kinase, and the progression through the cell cycle in cultured human fibroblasts. We found that cdk2 was activated and specifically localized to the nucleus during S phase and G2. Microinjection of affinity-purified anti-cdk2 antibodies but not of affinity-purified anti-cdc2 antibodies, during G1, inhibited entry into S phase. The specificity of these effects was demonstrated by the fact that a plasmid-driven cdk2 overexpression counteracted the inhibition. These results demonstrate that the cdk2 protein kinase is involved in the activation of DNA synthesis.

• MeSH
• buněčné linie MeSH
• buněčný cyklus * fyziologie   MeSH
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasy * MeSH
• fibroblasty * cytologie   MeSH
• fluorescenční protilátková technika MeSH
• inhibitory proteinkinas MeSH
• kinasy CDC2-CDC28 * MeSH
• kinetika MeSH
• lidé MeSH
• mikroinjekce MeSH
• molekulární sekvence - údaje MeSH
• protein-serin-threoninkinasy * MeSH
• proteinkinasy fyziologie   imunologie   MeSH
• replikace DNA MeSH
• sekvence aminokyselin MeSH
• specificita protilátek MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH