Marsters S A, Pitti R A, Sheridan J P, Ashkenazi A
Department of Molecular Oncology, Genentech, Inc, South San Francisco, California 94080, USA.
Recent Prog Horm Res. 1999;54:225-34.
Apo2 ligand (Apo2L, also called TRAIL) is a member of the tumor necrosis factor (TNF) cytokine family. The closest homolog of Apo2L is CD95 (Fas/Apo1) ligand, to which it has 24% amino acid sequence identity. Similar to CD95L, Apo2L activates rapid apoptosis in many types of cancer cells; however, whereas CD95L mRNA expression is restricted mainly to activated T cells, natural killer cells, and immune-privileged sites, Apo2L mRNA occurs in a wide variety of tissues. Most normal cells appear to be resistant to Apo2L's cytotoxic action, suggesting the existence of mechanisms that can protect against apoptosis induction by Apo2L. The first receptor described for Apo2L, called death receptor 4 (DR4), contains a cytoplasmic "death domain"; DR4 transmits the apoptosis signal carried by Apo2L. We have identified three additional receptors that bind to Apo2L. One receptor, called DR5, contains a cytoplasmic death domain and signals apoptosis much like DR4. The DR4 and DR5 mRNAs are expressed in many normal tissues and tumor cell lines. The second receptor, designated decoy receptor 1 (DcR1), is a phospholipid-anchored cell-surface protein that lacks a cytoplasmic tail. The third receptor, called DcR2, is structurally similar to DR4 and DR5 but has a truncated cytoplasmic death domain and does not transmit a death signal. The mRNAs for DcR1 and DcR2 are expressed in multiple normal tissues but in few tumor cell lines. Transfection experiments indicate that DcR1 and DcR2 act as decoys that prevent Apo2L from inducing apoptosis through DR4 and DR5. These decoy receptors thus represent a novel mechanism for regulating sensitivity to a pro-apoptotic cytokine directly at the cell's surface. The preferential expression of these inhibitory receptors in normal tissues suggests that Apo2L may be useful as an anticancer agent that induces apoptosis in cancer cells while sparing normal cells.
Apo2配体（Apo2L，也称为肿瘤坏死因子相关凋亡诱导配体）是肿瘤坏死因子（TNF）细胞因子家族的成员。Apo2L最接近的同源物是CD95（Fas/Apo1）配体，它们的氨基酸序列同一性为24%。与CD95L相似，Apo2L可在多种癌细胞中激活快速凋亡；然而，CD95L的mRNA表达主要局限于活化的T细胞、自然杀伤细胞和免疫赦免部位，而Apo2L的mRNA则存在于多种组织中。大多数正常细胞似乎对Apo2L的细胞毒性作用具有抗性，这表明存在能够防止Apo2L诱导凋亡的机制。第一个被描述的Apo2L受体称为死亡受体4（DR4），含有一个细胞质“死亡结构域”；DR4传递Apo2L携带的凋亡信号。我们已经鉴定出另外三种与Apo2L结合的受体。一种受体称为DR5，含有细胞质死亡结构域，其信号传导凋亡的方式与DR4非常相似。DR4和DR5的mRNA在许多正常组织和肿瘤细胞系中表达。第二种受体称为诱饵受体1（DcR1），是一种磷脂锚定的细胞表面蛋白，缺乏细胞质尾巴。第三种受体称为DcR2，在结构上与DR4和DR5相似，但具有截短的细胞质死亡结构域，不传递死亡信号。DcR1和DcR2的mRNA在多种正常组织中表达，但在少数肿瘤细胞系中表达。转染实验表明，DcR1和DcR2作为诱饵，可防止Apo2L通过DR4和DR5诱导凋亡。因此，这些诱饵受体代表了一种直接在细胞表面调节对促凋亡细胞因子敏感性的新机制。这些抑制性受体在正常组织中的优先表达表明，Apo2L可能是一种有用的抗癌药物，可诱导癌细胞凋亡，同时使正常细胞免受影响。
