Gastric mucosal injury activates bFGF gene expression and triggers preferential translation of high molecular weight bFGF isoforms through CUG-initiated, non-canonical codons
Gastric mucosal injury activates bFGF gene expression and triggers preferential translation of high molecular weight bFGF isoforms through CUG-initiated, non-canonical codons
复制标题
DOI：
10.1016/j.bbrc.2011.05.033
复制
发表时间：
2011-06-10
影响因子：
3.1
通讯作者：
Tarnawski, Andrzej S.
中科院分区：
文献类型：
--
作者：
Florkiewicz, Robert Z.;Ahluwalia, Amrita;Tarnawski, Andrzej S.
碱性成纤维细胞生长因子（bFGF或FGF-2）是一种多效生长因子，可促进间充质和上皮细胞的生长，刺激血管生成和神经保护。此外，外源性bFGF通过刺激血管生成促进胃十二指肠溃疡和心脏和脑损伤的愈合。所有这些作用都在18 kDa bFGF同种型方面得到证实，该同种型由细胞通过ER/Golgi非依赖性途径分泌并激活FGF受体。然而，在一些转化和应激的细胞和一些组织（例如脑）中，单拷贝bFGF基因编码多个基因产物：18 kDa和更高分子量（HMW）bFGF同种型：在啮齿动物中类似于21 kDa和类似于22 kDa，在人类中类似于22 kDa、类似于23 kDa和类似于24 kDa。这些HMW bFGF同种型在体内的生物学作用仍然未知。在这项研究中，我们表明，在正常的，未受伤的胃粘膜，bFGF几乎完全表达为18 kDa的异构体通过一个经典的AUG（蛋氨酸）密码子翻译。而在大鼠胃粘膜损伤中，bFGF基因通过选择性CUG（亮氨酸）起始密码子优先翻译为HMW bFGF亚型。大鼠胃粘膜损伤后8和24 h bFGF mRNA表达较正常粘膜显著增加，24-72 h bFGF蛋白表达显著增加，主要是由于与21和22 kDa HMW bFGF亚型相似的表达增加。这是第一次证明胃粘膜损伤和修复触发局部激活的bFGF基因与优先翻译的HMW bFGF异构体通过一个非典型的CUG密码子。这项研究揭示了CUG启动的HMW bFGF翻译作为一种新的调节机制，在体内胃损伤修复过程中运作。爱思唯尔公司出版
Basic fibroblast growth factor (bFGF or FGF-2) is a pleiotropic growth factor that promotes growth of mesenchymal and epithelial cells, stimulates angiogenesis and neuroprotection. Moreover, exogenous bFGF by stimulating angiogenesis promotes healing of gastroduodenal ulcers and cardiac and brain injury. All these actions were demonstrated in regard to 18 kDa bFGF isoform that is secreted by cells via an ER/Golgi-independent pathway and activates FGF receptors. However in some transformed and stressed cells and in some tissues (e.g. brain) the single copy bFGF gene encodes multiple gene products: 18 kDa and also higher molecular weight (HMW) bFGF isoforms: similar to 21 and similar to 22 kDa in rodents, and similar to 22, similar to 23 and similar to 24 kDa in humans. The biologic roles of these HMW bFGF isoforms in vivo remain unknown. In this study we demonstrated that in normal, uninjured gastric mucosa, bFGF is almost exclusively expressed as 18 kDa isoform translated through a classical AUG (methionine) codon. In contrast, in injured gastric mucosa of rat, bFGF gene is preferentially translated to HMW bFGF isoforms through alternative CUG (leucine) initiation codon. Gastric mucosal injury caused in rats a significant increase in bFGF mRNA at 8 and 24 h vs. normal mucosa and a significant increase in bFGF protein at 24-72 h, mainly due to increased expression of similar to 21 and similar to 22 kDa HMW bFGF isoforms. This is first demonstration that gastric mucosal injury and repair triggers local activation of bFGF gene with preferential translation of HMW bFGF isoforms through a non-canonical CUG codon. This study uncovered CUG-initiated HMW bFGF translation as a novel regulatory mechanism operating in vivo during gastric injury repair. Published by Elsevier Inc.