Gagarina Viktoria, Carlberg Alyssa L, Pereira-Mouries Lucilia, Hall David J
Cartilage Molecular Genetics Group, Cartilage Biology and Orthopedics Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892.
Cartilage Molecular Genetics Group, Cartilage Biology and Orthopedics Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892.
J Biol Chem. 2008 Jan 4;283(1):648-659. doi: 10.1074/jbc.M704035200. Epub 2007 Nov 8.
Cartilage oligomeric matrix protein (COMP) is a component of cartilage, synovium, ligament, and tendon, yet its normal function is largely unknown. To identify its function we have expressed it in 293 and HeLa cell lines and in primary human chondrocytes. We find that COMP protects these cells against death, either in the presence or absence of tumor necrosis factor alpha and is able to block activation of caspase 3, a critical effector caspase. This effect appears to be mediated by the IAP (inhibitor of apoptosis protein) family of anti-apoptotic proteins because the levels of XIAP, survivin, cIAP1 and cIAP2 are significantly elevated in the COMP-expressing cells and down-regulation of survivin and XIAP protein levels by small interfering RNAs blocks the ability of COMP to enhance survival. The mRNAs for most of the IAP family members were not increased by COMP, indicating that a translational/post-translational mechanism was involved in their induction. However, in both HeLa cells and chondrocytes, COMP induced survivin mRNA by 5-fold. Thus survivin is the first gene identified to be up-regulated transcriptionally by COMP. The carboxyl-terminal half of the protein comprising the type 3 repeats and the RGD sequence (CaCTD domain) was sufficient to promote survival and to elevate the IAPs. Further, an RGD peptide was able to block the prosurvival effect of COMP and the induction of XIAP and survivin, indicating that survival is likely mediated through integrin signaling. These data point to a new role for COMP in protecting cells against death.
软骨寡聚基质蛋白（COMP）是软骨、滑膜、韧带和肌腱的组成成分，但其正常功能在很大程度上尚不清楚。为了确定其功能，我们已在293和HeLa细胞系以及原代人软骨细胞中表达了该蛋白。我们发现，无论有无肿瘤坏死因子α，COMP都能保护这些细胞免于死亡，并且能够阻断关键效应半胱天冬酶3的激活。这种效应似乎是由抗凋亡蛋白的IAP（凋亡抑制蛋白）家族介导的，因为在表达COMP的细胞中，XIAP、生存素、cIAP1和cIAP2的水平显著升高，而通过小干扰RNA下调生存素和XIAP蛋白水平则会阻断COMP增强细胞存活的能力。COMP并未使大多数IAP家族成员的mRNA增加，这表明其诱导涉及翻译/翻译后机制。然而，在HeLa细胞和软骨细胞中，COMP均使生存素mRNA增加了5倍。因此，生存素是首个被鉴定为由COMP转录上调的基因。包含3型重复序列和RGD序列（CaCTD结构域）的蛋白羧基末端部分足以促进细胞存活并提高IAP水平。此外，RGD肽能够阻断COMP的促存活效应以及XIAP和生存素的诱导，这表明细胞存活可能是通过整合素信号传导介导的。这些数据表明COMP在保护细胞免于死亡方面具有新的作用。
