Bernard David, Gosselin Karo, Monte Didier, Vercamer Chantal, Bouali Fatima, Pourtier Albin, Vandenbunder Bernard, Abbadie Corinne
UMR 8117 CNRS-Institut Pasteur de Lille-Université Lille 1, Institut de Biologie de Lille, Lille Cedex, France.
Cancer Res. 2004 Jan 15;64(2):472-81. doi: 10.1158/0008-5472.can-03-0005.
After a finite doubling number, normal cells become senescent, i.e., nonproliferating and apoptosis resistant. Because Rel/nuclear factor (NF)-kappaB transcription factors regulate both proliferation and apoptosis, we have investigated their involvement in senescence. cRel overexpression in young normal keratinocytes results in premature senescence, as defined by proliferation blockage, apoptosis resistance, enlargement, and appearance of senescence-associated beta-galactosidase (SA-beta-Gal) activity. Normal senescent keratinocytes display a greater endogenous Rel/NF-kappaB DNA binding activity than young cells; inhibiting this activity in presenescent cells decreases the number of cells expressing the SA-beta-Gal marker. Normal senescent keratinocytes and cRel-induced premature senescent keratinocytes overexpressed manganese superoxide dismutase (MnSOD), a redox enzyme encoded by a Rel/NF-kappaB target gene. MnSOD transforms the toxic O()(2) into H(2)O(2), whereas catalase and glutathione peroxidase convert H(2)O(2) into H(2)O. Neither catalase nor glutathione peroxidase is up-regulated during cRel-induced premature senescence or during normal senescence, suggesting that H(2)O(2) accumulates. Quenching H(2)O(2) by catalase delays the occurrence of both normal and premature cRel-induced senescence. Conversely, adding a nontoxic dose of H(2)O(2) to the culture medium of young normal keratinocytes induces a premature senescence-like state. All these results indicate that Rel/NF-kappaB factors could take part in the occurrence of senescence by generating an oxidative stress via the induction of MnSOD.
在经过有限次数的倍增后，正常细胞会进入衰老状态，即不再增殖且具有抗凋亡能力。由于Rel/核因子（NF）-κB转录因子同时调节细胞增殖和凋亡，我们研究了它们在细胞衰老过程中的作用。在年轻的正常角质形成细胞中过表达cRel会导致过早衰老，其表现为增殖受阻、抗凋亡、细胞增大以及出现衰老相关的β-半乳糖苷酶（SA-β-Gal）活性。正常衰老的角质形成细胞比年轻细胞表现出更高的内源性Rel/NF-κB DNA结合活性；抑制衰老前细胞中的这种活性会减少表达SA-β-Gal标记的细胞数量。正常衰老的角质形成细胞和cRel诱导的过早衰老的角质形成细胞均过表达锰超氧化物歧化酶（MnSOD），这是一种由Rel/NF-κB靶基因编码的氧化还原酶。MnSOD将有毒的超氧阴离子（O₂⁻）转化为过氧化氢（H₂O₂），而过氧化氢酶和谷胱甘肽过氧化物酶则将H₂O₂转化为水（H₂O）。在cRel诱导的过早衰老或正常衰老过程中，过氧化氢酶和谷胱甘肽过氧化物酶均未上调，这表明H₂O₂会积累。用过氧化氢酶淬灭H₂O₂可延迟正常衰老和cRel诱导的过早衰老的发生。相反，向年轻正常角质形成细胞的培养基中添加无毒剂量的H₂O₂会诱导出类似过早衰老的状态。所有这些结果表明，Rel/NF-κB因子可能通过诱导MnSOD产生氧化应激而参与细胞衰老的发生。
