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J. Biol. Chem., Vol. 278, Issue 39, 37888-37894, September 26, 2003

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Ubiquitous Expression of the Forkhead Box M1B Transgene Accelerates Proliferation of Distinct Pulmonary Cell Types following Lung Injury^*

Vladimir V. Kalinichenko , Galina A. Gusarova  , Yongjun Tan , I-Ching Wang , Michael L. Major , Xinhe Wang , Helena M. Yoder  and Robert H. Costal  ¶

From the Department of Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60607-7170 and the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia

The delayed early transcription factor Forkhead Box M1B (FoxM1B) is expressed in proliferating cells, but its expression is extinguished in cells undergoing terminal differentiation. Liver regeneration studies with genetically altered mice that either prematurely expressed FoxM1B in hepatocytes or contained a hepatocyte-specific deletion of the Foxm1b allele demonstrated that FoxM1B is critical for regulating the expression of cell cycle genes required for hepatocyte proliferation. Furthermore, preventing the decline in hepatocyte FoxM1B levels during aging was sufficient to increase regenerating hepatocyte proliferation and expression of cell cycle genes to levels found in young regenerating mouse liver. Although these liver regeneration studies demonstrated that FoxM1B is required for hepatocyte proliferation, whether FoxM1B regulates proliferation of cell types other than hepatocytes remains to be determined. Here, we developed a new TG mouse line in which the –800-base pair Rosa26 promoter was used to drive expression of the FoxM1B transgene in all mouse tissues and found that Rosa26-FoxM1B TG mice were healthy, displaying no developmental defects. We used butylated hydroxytoluene (BHT) lung injury to demonstrate that premature expression of the FoxM1B transgene protein accelerated proliferation of different lung cell types, including alveolar type II epithelial cells, bronchial epithelial and smooth muscle cells, and endothelial cells of pulmonary capillaries and arteries. This was associated with the earlier expression of the cell cycle promoting cyclin A2, cyclin E, cyclin B1, cyclin F, and cyclin dependent kinase-1 (Cdk1) genes and diminished protein levels of Cdk inhibitor p21^Cip1. Taken together, these results suggest that increasing FoxM1B levels is an effective means to stimulate cellular proliferation during aging and in lung diseases such as emphysema.

Received for publication, May 28, 2003 , and in revised form, June 26, 2003.

^* This work was supported by NIDDK, National Institutes of Health Grant RO1 DK 54687-05 and NIA, National Institutes of Health Grant RO1 AG 21842-01 (both to R. H. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Molecular Genetics (M/C 669), University of Illinois at Chicago, College of Medicine, 900 S. Ashland Ave., Rm. 2220 MBRB, Chicago, IL 60607-7170. Tel.: 312-996-0474; Fax: 312-355-4010; E-mail: Robcosta{at}uic.edu.

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