RESUMO
Chemotherapy and radiation, the two most common cancer therapies, exert their anticancer effects by causing damage to cellular DNA. However, systemic treatment damages DNA not only in cancer, but also in healthy cells, resulting in the progression of serious side effects and limiting efficacy of the treatment. Interestingly, in response to DNA damage, p53 seems to play an opposite role in normal and in the majority of cancer cells-wild-type p53 mediates apoptosis in healthy tissues, attributing to the side effects, whereas mutant p53 often is responsible for acquired cancer resistance to the treatment. Here, we show that leucine zipper-containing ARF-binding protein (LZAP) binds and stabilizes p53. LZAP depletion eliminates p53 protein independently of its mutation status, subsequently protecting wild-type p53 cells from DNA damage-induced cell death, while rendering cells expressing mutant p53 more sensitive to the treatment. In human non-small-cell lung cancer, LZAP levels correlated with p53 levels, suggesting that loss of LZAP may represent a novel mechanism of p53 inactivation in human cancer. Our studies establish LZAP as a p53 regulator and p53-dependent determinative of cell fate in response to DNA damaging treatment.
RESUMO
The effect of recombinant TNF-α on programmed death of donor lymphocytes was studied in vitro. The proapoptotic effect of this cytokine is realized through transcription factors and cell cycle inhibitors. Incubation of lymphocytes with recombinant TNF-α revealed increased levels of NF-kB and p21 and reducted content of nonphosphorylated p53.
Assuntos
Apoptose/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Linfócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Adulto , Apoptose/fisiologia , Feminino , Citometria de Fluxo , Humanos , Técnicas In Vitro , Linfócitos/fisiologia , Masculino , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
We studied the in vitro apoptosis-inducing effect of recombinant TNF-α (rTNF-α) on blood lymphocytes from healthy donors. rTNF-α-induced apoptosis was accompanied by an increase in the number of cells with low mitochondrial transmembrane potential, increased intracellular content of reactive oxygen species, reduced content of Bcl-2, Bcl-xL, and Bax proteins, and elevated Bad content. The molecular mechanisms of these changes are discussed.
Assuntos
Apoptose/fisiologia , Linfócitos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Caspases/metabolismo , Feminino , Humanos , Técnicas In Vitro , Linfócitos/citologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Estatísticas não ParamétricasRESUMO
The effects of recombinant IL-2 on apoptosis of lymphocytes of healthy donors were studied in in vitro experiments. It was shown that the inductive and inhibitory effects of IL-2 on apoptotic process depend on the dose of the cytokine and cell microenvironmental conditions. Culturing of lymphocytes with recombinant IL-2 increases the percent of cells with reduced transmembrane potential, reduces the content of intracellular proteins Bcl-2, Bcl-X(L) and и Bax, and increases the level of Bad. The proapoptotic effect of this cytokine is realized with participation of nuclear transcription factor NF-κB and transcription factor P53.
