Progranulin: a growth factor, a novel TNFR ligand and a drug target.
Progranulin: a growth factor, a novel TNFR ligand and a drug target.
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促生蛋白：一种生长因子，一种新型的TNFR配体和药物靶标。
DOI：
10.1016/j.pharmthera.2011.10.003
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发表时间：
2012-01
影响因子：
13.5
通讯作者：
Bosch, Xavier
中科院分区：
文献类型：
--
作者：
Liu, Chuan-ju;Bosch, Xavier
原颗粒蛋白(PGRN)在上皮细胞、免疫细胞、神经元和软骨细胞中大量表达，并被认为与肿瘤的发生有关。PGRN是伤口愈合和组织修复的重要介质。PGRN也是一种神经营养因子，PGRN基因突变导致PGRN蛋白部分丢失会导致额颞部痴呆。PGRN是一种新型的软骨细胞生长因子，在软骨发育和炎症性关节炎中发挥重要作用。尽管研究表明PGRN具有抗炎作用，但关于这种作用的确切分子途径，特别是PGRN结合受体的详细信息，到目前为止还没有确定。近年来，研究人员发现PGRN与肿瘤坏死因子受体结合，干扰肿瘤坏死因子α与肿瘤坏死因子受体之间的相互作用。他们进一步证明，缺乏PGRN的小鼠容易患上胶原诱导性关节炎，这是类风湿性关节炎的实验模型，并且给予PGRN逆转了关节炎的过程。一种由三个PGRN片段组成的工程蛋白(Atsttrin)，显示出选择性的TNFR结合，比天然的PGRN更有活性。前列腺素RN和爱特林均可预防各种关节炎小鼠模型的炎症反应，并抑制肿瘤坏死因子α诱导的细胞内信号通路。因此，PGRN是炎症的关键调节因子，它可能至少部分地通过阻断肿瘤坏死因子与其受体的结合来介导其抗炎作用。正如我们在这里讨论的，基于TNFR的干预可能既刺激又抑制癌细胞的生长，同样的情况也可能适用于Atsttrin作为新参与者的类比。
Progranulin (PGRN) is abundantly expressed in epithelial cells, immune cells, neurons, and chondrocytes, and reportedly contributes to tumorigenesis. PGRN is a crucial mediator of wound healing and tissue repair. PGRN also functions as a neurotrophic factor and mutations in the PGRN gene resulting in partial loss of the PGRN protein cause frontotemporal dementia. PGRN has been found to be a novel chondrogenic growth factor and to play an important role in cartilage development and inflammatory arthritis. Although research has shown that PGRN exhibits anti-inflammatory properties, the details about the exact molecular pathway of such effects, and, in particular, the PGRN binding receptor, have not been identified so far. Recently, researchers have shown that PGRN binds to tumor necrosis factor (TNF)-receptors (TNFR), interfering with the interaction between TNFα and TNFR. They further demonstrated that mice deficient in PGRN are susceptible to collagen-induced arthritis, an experimental model of rheumatoid arthritis, and that administration of PGRN reversed the arthritic process. An engineered protein made of three PGRN fragments (Atsttrin), displayed selective TNFR binding and was more active than natural PGRN. Both PGRN and Atsttrin prevented inflammation in various arthritis mouse models and inhibited TNFα-induced intracellular signaling pathways. Thus, PGRN is a key regulator of inflammation and it may mediate its anti-inflammatory effects, at least in part, by blocking TNF binding to its receptors. As we discuss here, TNFR-based interventions may both stimulate and suppress the growth of cancer cells, and the same may be true in analogy for Atsttrin as a new player.
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