O'Connell M J, Chua R, Hoyos B, Buck J, Chen Y, Derguini F, Hämmerling U
Program in Immunology, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York 10021, USA.
J Exp Med. 1996 Aug 1;184(2):549-55. doi: 10.1084/jem.184.2.549.
Vitamin A serves as a prohormone from which three classes of active metabolites are derived: the aldehydes, the carboxylic acids, and the retro-retinoids. Although these three classes are united under the rubric of signal transduction, they act by different molecular mechanisms: the 11-cis-retinaldehydes combine with opsin to form the universal visual pigments and the retinoic acids form ligands for transcription factors, whereas the retro-retinoids, as shown here, intersect with signal transduction at a cytoplasmic or membrane site. The retro-retinoid, anhydroretinol (AR), has long been known to act as a growth inhibitor in lymphocytes, whereas 14-hydroxy-4,14-retro-retinol (14-HRR) is required for normal lymphocyte proliferation. A mutually reversible relationship exists between these two retro-retinoids as one can reverse the effects of the other when given in pharmacological doses. The common explanation for reversible inhibition is competition for a shared receptor. We now provide evidence that when AR is given to T cells unmitigated by 14-HRR, rapid cell death can occur. The circumstances are closely related to nonclassical forms of apoptosis: within 2 h of AR administration the T cells undergo widespread morphological changes, notably surface blebbing and ballooning and, inevitably, bursting. In contrast, nuclear changes are comparatively mild, as indicated by absence of chromatin condensation and overt DNA cleavage to discrete nucleosomal fragments, although DNA nicks are readily discernible by terminal deoxynucleotidyl transferase assay. What further distinguishes the AR-induced form of apoptosis from classical ones is a lack of requirements of messenger RNA and protein synthesis, suggesting that the events leading to cell death are primarily initiated and play themselves out in the cytoplasm. This view is further reinforced by the finding that herbimycin A can prevent the onset of programmed cell death. The importance of our findings is that they strongly suggest a second messenger role for vitamin A metabolites in the cytoplasmic realm that has not been seen previously. These findings are entirely compatible with a general notion that in a cell requiring multiple coordinated signals for survival, the provision of an unbalanced signal can initiate programmed cell death. Collectively, our data also challenge the paradigm that retinoids (outside vision) solely mediate their function via the steroid/ retinoic acid receptor family of nuclear transcription factors. Instead, a mode of action in the cytoplasmic realm akin to one attributed to other small lipophilic second messenger molecules, such as diacyl glycerol or ceramide, may apply to retro-retinoids.
维生素A作为一种前体激素，可衍生出三类活性代谢产物：醛类、羧酸类和逆转视黄醛类。尽管这三类物质都归在信号转导这一类别之下，但它们的作用分子机制各不相同：11-顺式视黄醛与视蛋白结合形成通用视觉色素，视黄酸则形成转录因子的配体，而如图所示，逆转视黄醛类在细胞质或膜位点与信号转导相互作用。长期以来已知逆转视黄醛脱水视黄醇（AR）在淋巴细胞中起生长抑制剂的作用，而正常淋巴细胞增殖需要14-羟基-4,14-逆转视黄醇（14-HRR）。这两种逆转视黄醛之间存在相互可逆的关系，因为当以药理剂量给予时，一种可以逆转另一种的作用。对可逆抑制的常见解释是对共享受体的竞争。我们现在提供证据表明，当未用14-HRR缓解的AR给予T细胞时，会发生快速细胞死亡。这种情况与非经典形式的细胞凋亡密切相关：在给予AR后2小时内，T细胞会发生广泛的形态变化，特别是表面起泡和肿胀，最终破裂。相比之下，核变化相对较轻，如染色质凝聚和DNA明显切割成离散核小体片段的缺失所示，尽管通过末端脱氧核苷酸转移酶测定很容易检测到DNA切口。AR诱导的细胞凋亡形式与经典形式的进一步区别在于不需要信使RNA和蛋白质合成，这表明导致细胞死亡的事件主要在细胞质中启动并自行发生。除草霉素A可以预防程序性细胞死亡的发生这一发现进一步强化了这一观点。我们研究结果的重要性在于，它们强烈暗示维生素A代谢产物在细胞质领域中具有以前未见过的第二信使作用。这些发现与一个普遍观念完全一致，即在一个需要多个协调信号才能存活的细胞中，提供不平衡的信号可以引发程序性细胞死亡。总体而言，我们的数据也挑战了视黄醛（视觉之外）仅通过核转录因子的类固醇/视黄酸受体家族介导其功能的范式。相反，一种类似于归因于其他小的亲脂性第二信使分子（如二酰甘油或神经酰胺）的细胞质领域作用模式可能适用于逆转视黄醛类。
