A Direct In?Vivo RNAi Screen Identifies MKK4 as a Key Regulator of Liver Regeneration

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• 作者：Torsten Wuestefeld¹ ; ² ; ³ ; Marina Pesic² ; ³ ; Ramona Rudalska² ; ³ ; Daniel Dauch² ; ³ ; Thomas Longerich⁵ ; Tae-Won Kang² ; ³ ; Tetyana Yevsa¹ ; Florian Heinzmann² ; ³ ; Lisa Hoenicke² ; ³ ; Anja Hohmeyer¹ ; ³ ; Anna Potapova² ; Ina Rittelmeier¹ ; ⁶ ; Michael Jarek² ; Robert Geffers² ; Maren Scharfe² ; Frank Klawonn² ; Peter Schirmacher⁵ ; Nisar P. Malek⁴ ; Michael Ott¹ ; ⁶ ; Alfred Nordheim⁷ ; Arndt Vogel¹ ; Michael P. Manns¹ ; Lars Zender¹ ; ² ; ³ ; ^{lars.zender@med.uni-tuebingen.de}
• 刊名：Cell
• 出版年：2013
• 出版时间：11 April, 2013
• 年：2013
• 卷：153
• 期：2
• 页码：389-401
• 全文大小：1686 K

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Summary

The liver harbors a distinct capacity for endogenous regeneration; however, liver regeneration is often impaired in disease and therefore insufficient to compensate for the loss of hepatocytes and organ function. Here we describe a functional genetic approach for the identification of gene targets that can be exploited to increase the regenerative capacity of hepatocytes. Pools of small hairpin RNAs (shRNAs) were directly and stably delivered into mouse livers to screen for genes modulating liver regeneration. Our studies identify the dual-specific kinase MKK4 as a master regulator of liver regeneration. MKK4 silencing robustly increased the regenerative capacity of hepatocytes in mouse models of liver regeneration and acute and chronic liver failure. Mechanistically, induction of MKK7 and a JNK1-dependent activation of the AP1 transcription factor ATF2 and the Ets factor ELK1 are crucial for increased regeneration of hepatocytes with MKK4 silencing.