RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy
RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy
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DOI：
10.1073/pnas.0407378102
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发表时间：
2004-12-28
影响因子：
11.1
通讯作者：
Naor, D
中科院分区：
文献类型：
--
作者：
Nedvetzki, S;Gonen, E;Naor, D
我们在这里报告，在胶原诱导的关节炎中，CD44基因敲除小鼠的关节炎比WT小鼠的关节炎更严重，我们提供了分子冗余作为致病因素的证据。此外，我们表明，在炎症级联反应下，RHAMM（透明质酸介导的运动性受体），一种不同于CD44的透明质酸受体，弥补了CD44结合透明质酸的损失，支持细胞迁移，上调与炎症相关的基因（通过含有13，000个cDNA克隆的微阵列评估），并加剧胶原诱导的关节炎。有趣的是，我们进一步发现，对CD44基因丢失的补偿并不是因为冗余基因（RHAMM）的表达增强而发生的，而是因为CD44的丢失允许透明质酸底物的积累增加，CD44和RHAMM两者都与透明质酸底物结合，从而能够通过RHAMM增强信号传导。这个模型启发了分子冗余的几个方面，这在许多科学界被广泛讨论，但过程仍然是不明确的。
We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined.