Stathmin 1 Induces Murine Hepatocyte Proliferation and Increased Liver Mass

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.