Involvement of Rd/nuclear factor-κB transcription factors in keratinocyte senescence
Involvement of Rd/nuclear factor-κB transcription factors in keratinocyte senescence
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DOI：
10.1158/0008-5472.can-03-0005
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发表时间：
2004-01-15
期刊：
影响因子：
11.2
通讯作者：
Abbadie, C
中科院分区：
文献类型：
--
作者：
Bernard, D;Gosselin, K;Abbadie, C
经过有限的翻倍后，正常细胞就会衰老，即，不增殖和抗凋亡。由于Rel/核因子（NF）-κ B转录因子调节增殖和凋亡，我们已经研究了它们参与衰老。年轻正常角质形成细胞中的cRel过表达导致过早衰老，如通过增殖阻断、凋亡抗性、增大和衰老相关β-半乳糖苷酶（SA-β-Gal）活性的出现所定义的。正常衰老的角质形成细胞显示出比年轻细胞更大的内源性Rel/NF-κ B DNA结合活性;在衰老细胞中抑制这种活性会减少表达SA-β-Gal标记物的细胞数量。正常衰老角质形成细胞和cRel诱导的过早衰老角质形成细胞过表达锰超氧化物歧化酶（MnSOD），一种由Rel/NF-κ B靶基因编码的氧化还原酶。MnSOD将有毒的O（-）转化为H2 O2，而过氧化氢酶和谷胱甘肽过氧化物酶将H2 O2转化为H2O。无论是过氧化氢酶，谷胱甘肽过氧化物酶是上调crel诱导的早衰或在正常衰老过程中，这表明过氧化氢积累。通过过氧化氢酶淬灭H2 O2延迟了正常和过早cRel诱导的衰老的发生。相反，向年轻的正常角质形成细胞的培养基中加入无毒剂量的H2 O2会诱导过早衰老样状态。所有这些结果表明Rel/NF-kappaB因子可能通过诱导MnSOD产生氧化应激来参与衰老的发生。
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(-) into H2O2, whereas catalase and glutathione peroxidase convert H2O2 into H2O. Neither catalase nor glutathione peroxidase is up-regulated during cRel-induced premature senescence or during normal senescence, suggesting that H2O2 accumulates. Quenching H2O2 by catalase delays the occurrence of both normal and premature cRel-induced senescence. Conversely, adding a nontoxic dose of H2O2 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.