Chinnadurai G, Vijayalingam S, Gibson S B
Institute for Molecular Virology, Doisy Research Center, Saint Louis University Medical Center, St Louis, MO 63104, USA.
Oncogene. 2008 Dec;27 Suppl 1(Suppl 1):S114-27. doi: 10.1038/onc.2009.49.
The BNIP3 subfamily of BH3-only proteins consists of BNIP3 and BNIP3-like (BNIP3L) proteins. These proteins form stable homodimerization complexes that localize to the outer membrane of the mitochondria after cellular stress. This promotes either apoptotic or non-apoptotic cell death such as autophagic cell death. Although the mammalian cells contain both members of this subfamily, the genome of Caenorhabditis elegans codes for a single BNIP3 ortholog, ceBNIP3, which shares homology in the transmembrane (TM) domain and in a conserved region close to the BH3 domain of mammalian BNIP3 protein. The cell death activities of BNIP3 and BNIP3L are determined by either the BH3 domain or the C-terminal TM domain. The TM domain of BNIP3 is unique, as it is capable of autonomous stable dimerization and contributes to mitochondrial localization of BNIP3. In knockout mouse models, BNIP3L was shown to be essential for normal erythrocyte differentiation and hematopoietic homeostasis, whereas BNIP3 plays a role in cellular responses to ischemia/reperfusion injury in the heart. Both BNIP3 and BNIP3L play a role in cellular responses to stress. Under hypoxia, both BNIP3 and BNIP3L expression levels are elevated and contribute to hypoxia-induced cell death. In addition, these proteins play critical roles in disease states. In heart disease, both BNIP3 and BNIP3L play a critical role in cardiomyocyte cell death following ischemic and non-ischemic injuries. In cancer, expression of BNIP3 and BNIP3L is downregulated by promoter hypermethylation or by homozygous deletion of the gene locus in certain cancers, whereas their expression was increased in other cancers. In addition, BNIP3 expression has been correlated with poor prognosis in some cancers. The results reviewed here suggest that BNIP3 and BNIP3L may be novel therapeutic targets for intervention because of their pathological roles in regulating cell death in disease states.
仅含BH3结构域的蛋白质的BNIP3亚家族由BNIP3和BNIP3样（BNIP3L）蛋白质组成。这些蛋白质形成稳定的同二聚体复合物，在细胞应激后定位于线粒体的外膜。这会促进凋亡性或非凋亡性细胞死亡，如自噬性细胞死亡。尽管哺乳动物细胞含有该亚家族的两个成员，但秀丽隐杆线虫的基因组编码单个BNIP3直系同源物ceBNIP3，它在跨膜（TM）结构域以及靠近哺乳动物BNIP3蛋白BH3结构域的保守区域具有同源性。BNIP3和BNIP3L的细胞死亡活性由BH3结构域或C末端TM结构域决定。BNIP3的TM结构域很独特，因为它能够自主稳定二聚化，并有助于BNIP3定位于线粒体。在基因敲除小鼠模型中，BNIP3L被证明对正常红细胞分化和造血稳态至关重要，而BNIP3在心脏对缺血/再灌注损伤的细胞反应中起作用。BNIP3和BNIP3L在细胞对应激的反应中均起作用。在缺氧条件下，BNIP3和BNIP3L的表达水平均升高，并导致缺氧诱导的细胞死亡。此外，这些蛋白质在疾病状态中起关键作用。在心脏病中，BNIP3和BNIP3L在缺血性和非缺血性损伤后的心肌细胞死亡中均起关键作用。在癌症中，在某些癌症中，BNIP3和BNIP3L的表达因启动子高甲基化或基因座的纯合缺失而下调，而在其他癌症中它们的表达则增加。此外，BNIP3的表达与某些癌症的不良预后相关。此处综述的结果表明，由于BNIP3和BNIP3L在疾病状态下调节细胞死亡的病理作用，它们可能是新的治疗干预靶点。
