p8-deficient fibroblasts grow more rapidly and are more resistant to adriamycin-induced apoptosis.
p8 is a stress-induced DNA-binding protein, biochemically related to the architectural chromatin binding HMG protein family and whose function is presently unknown. We obtained fibroblast from mice lacking p8 and found that p8 is involved in cell growth regulation and in apoptosis. p8(-/-) mouse embryonic fibroblasts (MEFs) grow more rapidly than p8(+/+) MEFs. This might be explained by the higher intracellular level and activity of the Cdk2 and Cdk4 observed in p8(-/-) MEFs, which in turn may result, at least in part, from the concomitant decrease observed in the amount of cyclin-dependent kinase inhibitor p27. We also report that p8 mRNA expression is strongly activated in fibroblasts after cell growth arrest induced by serum deprivation or confluence. As expected, MEFs expressing p8 arrest their growth more rapidly after serum deprivation than MEFs lacking p8, which strongly suggests that p8 over-expression is implicated in cell growth arrest. On the other hand, p8(+/+) MEFs are more sensitive than p8(-/-) MEFs to the apoptosis induced by adriamycin treatment. p53 might be involved, as p8 expression increases its intracellular amount and trans-activation capacity. Finally, demonstration that p53 is a negative trans-activator of p8 suggests the presence of a complex autoregulatory loop. In conclusion, p8 is a cell growth inhibitor that facilitates apoptosis induced in fibroblasts by DNA damage.
Vasseur
Sophie
S
Centre de Recherche INSERM, EMI 0116, Parc Scientifique et Technologique de Luminy, 163 Av. de Luminy, F-13009 Marseille, France.
Hoffmeister
Albrecht
A
Garcia-Montero
Andrés
A
Mallo
Gustavo Vidal
GV
Feil
Robert
R
Kühbandner
Susanne
S
Dagorn
Jean-Charles
JC
Iovanna
Juan Lucio
JL
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006133:Growth Substances / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins; D012333:RNA, Messenger / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000903:Antibiotics, Antineoplastic; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D006133:Growth Substances; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin