Details

Autor(en) / Beteiligte

• Armeni, Tatiana
• Ercolani, Luisa
• Urbanelli, Lorena
• Magini, Alessandro
• Magherini, Francesca
• Pugnaloni, Armanda
• Piva, Francesco
• Modesti, Alessandra
• Emiliani, Carla
• Principato, Giovanni
• Sherman, Michael

Titel

Cellular redox imbalance and changes of protein S-glutathionylation patterns are associated with senescence induced by oncogenic H-ras

Ist Teil von

• PloS one, 2012-12, Vol.7 (12), p.e52151-e52151

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• H-Ras oncogene requires deregulation of additional oncogenes or inactivation of tumor suppressor proteins to increase cell proliferation rate and transform cells. In fact, the expression of the constitutively activated H-RasV12 induces cell growth arrest and premature senescence, which act like barriers in pre-neoplastic lesions. In our experimental model, human fibroblasts transfected with H-RasV12 show a dramatic modification of morphology. H-RasV12 expressing cells also show premature senescence followed by cell death, induced by autophagy and apoptosis. In this context, we provide evidence that in H-RasV12 expressing cells, the premature senescence is associated with cellular redox imbalance as well as with altered post-translation protein modification. In particular, redox imbalance is due to a strong reduction of total antioxidant capacity, and significant decrease of glutathione level. As the reversible addition of glutathione to cysteinyl residues of proteins is an important post-translational regulative modification, we investigated S-glutathionylation in cells expressing active H-Ras. In this contest we observed different S-glutathionylation patterns in control and H-RasV12 expressing cells. Particularly, the GAPDH enzyme showed S-glutathionylation increase and significant enzyme activity depletion in H-Ras V12 cells. In conclusion, we proposed that antioxidant defense reduction, glutathione depletion and subsequent modification of S-glutathionylation of target proteins contribute to arrest cell growth, leading to death of fibroblasts expressing constitutively active H-Ras oncogene, thus acting as oncogenic barriers that obstacle the progression of cell transformation.