Mutation of a major keratin phosphorylation site predisposes to hepatotoxic injury in transgenic mice.
Mutation of a major keratin phosphorylation site predisposes to hepatotoxic injury in transgenic mice.
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DOI：
10.1083/jcb.143.7.2023
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发表时间：
1998-12-28
期刊：
影响因子：
--
通讯作者：
Omary MB
中科院分区：
文献类型：
--
作者：
Ku NO;Michie SA;Soetikno RM;Resurreccion EZ;Broome RL;Omary MB
单纯上皮表达角蛋白8（K8）和18（K18）作为其主要中间丝（IF）蛋白。K8/18的一个重要生理功能是保护肝细胞免受药物诱导的肝损伤。虽然这种保护的机制是未知的，显着的K8/18过度磷酸化与各种细胞应激和有丝分裂过程中发生。这种角蛋白磷酸化的增加涉及多个位点，包括人K18丝氨酸-（ser）52，其是主要的K18磷酸化位点。我们研究了角蛋白过度磷酸化的意义，并通过产生过表达人基因组K18 ser 52 → ala突变体（S52 A）的转基因小鼠，并将其与过表达类似水平野生型（WT）人K18的小鼠进行比较，重点关注K18 ser 52。废除K18丝氨酸52磷酸化不影响纤维组织后，部分肝切除术，也没有小鼠肝脏再生的能力。然而，与WT K18表达小鼠相比，S52 A表达小鼠暴露于与K18 ser 52和其他角蛋白磷酸化变化相关的肝毒素灰黄霉素或微囊藻毒素导致更显著的肝毒性。我们的研究结果表明，K18 ser 52磷酸化在保护肝细胞免受应激诱导的肝损伤中起着生理作用。由于肝毒素与多个位点的角蛋白磷酸化增加有关，因此除了K18 ser 52和其他IF蛋白上的磷酸化位点之外，可能还有独特的位点也参与保护细胞免受应激。
Simple epithelia express keratins 8 (K8) and 18 (K18) as their major intermediate filament (IF) proteins. One important physiologic function of K8/18 is to protect hepatocytes from drug-induced liver injury. Although the mechanism of this protection is unknown, marked K8/18 hyperphosphorylation occurs in association with a variety of cell stresses and during mitosis. This increase in keratin phosphorylation involves multiple sites including human K18 serine-(ser)52, which is a major K18 phosphorylation site. We studied the significance of keratin hyperphosphorylation and focused on K18 ser52 by generating transgenic mice that overexpress a human genomic K18 ser52→ ala mutant (S52A) and compared them with mice that overexpress, at similar levels, wild-type (WT) human K18. Abrogation of K18 ser52 phosphorylation did not affect filament organization after partial hepatectomy nor the ability of mouse livers to regenerate. However, exposure of S52A-expressing mice to the hepatotoxins, griseofulvin or microcystin, which are associated with K18 ser52 and other keratin phosphorylation changes, resulted in more dramatic hepatotoxicity as compared with WT K18-expressing mice. Our results demonstrate that K18 ser52 phosphorylation plays a physiologic role in protecting hepatocytes from stress-induced liver injury. Since hepatotoxins are associated with increased keratin phosphorylation at multiple sites, it is likely that unique sites aside from K18 ser52, and phosphorylation sites on other IF proteins, also participate in protection from cell stress.
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DOI：
10.1083/jcb.127.1.161
发表时间：
1994-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ku NO;Omary MB
通讯作者：
Omary MB
DOI：
10.1006/bbrc.1995.2475
发表时间：
1995-10-04
影响因子：
3.1
作者：
GOU, JP;EYER, J;LETERRIER, JF
通讯作者：
LETERRIER, JF
影响因子：
11.4
作者：
Ku, NO;Liao, J;Omary, MB
通讯作者：
Omary, MB
影响因子：
10.5
作者：
BARIBAULT, H;PENNER, J;WILSONHEINER, M
通讯作者：
WILSONHEINER, M
影响因子：
158.5
作者：
Jochimsen, EM;Carmichael, WW;Jarvis, WR
通讯作者：
Jarvis, WR