INSERM U.1014, Batiment Lavoisier, Hôpital Paul Brousse, 14 Avenue Paul Vaillant Couturier, 94807 Villejuif, France.
Apoptosis. 2010 Dec;15(12):1529-39. doi: 10.1007/s10495-010-0528-2.
The protein Puma (p53-upregulated modulator of apoptosis) belongs to the BH3-only group of the Bcl-2 family and is a major regulator of apoptosis. Although the transcriptional regulation of Puma is clearly established, little is known about the regulation of its expression at the protein levels. We show here that various signals--including the cytokine TGFβ, the death effector TRAIL or chemical drugs such as anisomycin--downregulate Puma protein levels via a novel pathway based on the sequential activation of caspase-3 and a protease inhibited by the serpase inhibitor N-tosyl-L-phenylalanine chloromethyl ketone. This pathway is specific for Puma because (1) the levels of other BH3-only proteins, such as Bim and Noxa were not modified by these stimuli and (2) this caspase-mediated degradation was dependent on both the BH3 and C-terminal domains of Puma. Our data also show that Puma is regulated during the caspase-3-dependent differentiation of murine embryonic stem cells and suggest that this pathway may be relevant and important during caspase-mediated cell differentiation not associated with apoptosis.
蛋白 Puma（p53 上调的凋亡调节剂）属于 Bcl-2 家族的 BH3 仅家族成员，是细胞凋亡的主要调节因子。虽然 Puma 的转录调控已明确，但对其蛋白质水平的表达调控知之甚少。我们在此表明，包括细胞因子 TGFβ、死亡效应因子 TRAIL 或化学药物如放线菌酮在内的各种信号通过基于半胱天冬酶-3 的顺序激活和丝氨酸蛋白酶抑制剂 N-对甲苯磺酰-L-苯丙氨酸氯甲基酮抑制的蛋白酶的新型途径下调 Puma 蛋白水平。该途径是特异性针对 Puma 的，因为 (1) 其他 BH3 仅蛋白，如 Bim 和 Noxa 的水平不受这些刺激的影响，(2) 这种半胱天冬酶介导的降解依赖于 Puma 的 BH3 和 C 末端结构域。我们的数据还表明，在小鼠胚胎干细胞的 caspase-3 依赖性分化过程中 Puma 受到调节，并表明该途径可能与 caspase 介导的不涉及凋亡的细胞分化有关且非常重要。
