Stathmin 1 Induces Murine Hepatocyte Proliferation and Increased Liver Mass.

• Type of Material: Article
• Authors: Enpeng Zhao, Icahn School of Medicine at Mount Sinai; Yang Shen, Emory University; Muhammad Amir, Emory University; Alton B Farris III, Emory University; Mark Czaja, Emory University
• Language: English
• Date: 2020-01
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial No Derivatives
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/hep4.1447
• Title of Journal or Parent Work: Hepatology Communications
• ISSN: 2471-254X
• Volume: 4
• Issue: 1
• Start Page: 38
• End Page: 49
• Grant/Funding Information: Supported by the National Institutes of Health (grants R01DK044234 to M.J.C. and T32DK108735 to M.A.).
• Keywords: adenovirus; green fluorescent protein; polymerase chain reaction; BrdU; cyclin-dependent kinase; messenger RNA; stathmin 1; alanine aminotransferase
• Research Categories: Biology, Genetics; Health Sciences, Pathology

Abstract

The endogenous cellular signals that initiate the transition of hepatocytes from quiescence to proliferation remain unclear. The protein stathmin 1 (STMN1) is highly expressed in dividing cells, including hepatocytes, and functions to promote cell mitosis through physical interactions with tubulin and microtubules that regulate mitotic spindle formation. The recent finding that STMN1 mediates the resistance of cultured hepatocytes to oxidant stress led to an examination of the expression and function of this protein in the liver in vivo. STMN1 messenger RNA (mRNA) and protein were essentially undetectable in normal mouse liver but increased markedly in response to oxidant injury from carbon tetrachloride. Similarly, levels of STMN1 mRNA and protein were increased in human livers from patients with acute fulminant hepatic failure. To determine STMN1 function in the liver in vivo, mice were infected with a control or Stmn1-expressing adenovirus. Stmn1 expression induced spontaneous liver enlargement with a doubling of the liver to body weight ratio. The increase in liver mass resulted, in part, from hepatocellular hypertrophy but mainly from an induction of hepatocyte proliferation. STMN1 expression led to marked increases in the numbers of 5-bromo-2'-deoxyuridine-positive and mitotic hepatocytes and hepatic nuclear levels of cyclins and cyclin-dependent kinases. STMN1-induced hepatocyte proliferation was followed by an apoptotic response and a return of the liver to its normal mass. Conclusion: STMN1 promotes entry of quiescent hepatocytes into the cell cycle. STMN1 expression by itself in the absence of any reduction in liver mass is sufficient to stimulate a hepatic proliferative response that significantly increases liver mass.