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Papers In Press, published online ahead of print December 18, 2001
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871
Corresponding Author: nakamura{at}imed3.med.osaka-u.ac.jp
Hepatoma-derived growth factor (HDGF) is the original member of the HDGF family of proteins, which contain a well-conserved N-terminal amino acid sequence (homologous to the amino terminus of HDGF; hath) and nuclear localization signals (NLSs) in gene-specific regions other than the hath region. In addition to a bipartite NLS in a gene-specific region, an NLS-like sequence is also found in the hath region. In cells expressing green fluorescence protein (GFP)-HDGF, green fluorescence was observed in the nucleus, whereas it was detected in the cytoplasm of cells expressing GFP-HDGF with both NLSs mutated or deleted. GFP-hath protein (GFP-HATH) was distributed mainly in the nucleus although some was present in the cytoplasm, while GFP-HDGF with a deleted hath region (HDGFnonHATH) was found only in the nucleus. Exogenously supplied GFP-HDGF was internalized and translocated to the nucleus. GFP-HATH was internalized, whereas GFP-HDGFnonHATH was not. Overexpression of HDGF stimulated DNA synthesis and cellular proliferation, although HDGF with both NLSs deleted did not. Overexpression of HDGFnonHATH caused a significant stimulation of DNA synthesis, while that of hath protein did not. HDGF containing the NLS sequence of p53 instead of the bipartite NLS did not stimulate DNA synthesis, and also truncated forms without the C-terminal or N-terminal side of NLS2 did not. These findings suggest that the gene-specific region, at least the bipartite NLS sequence and the N-terminal and C-terminal neighboring portions, is essential for the mitogenic activity of HDGF after nuclear translocation.
J. Biol. Chem, 10.1074/jbc.M111122200
Submitted on November 20, 2001
Revised on December 18, 2001
Accepted on December 17, 2001
Hepatoma-derived growth factor stimulates cell growth after translocation to the nucleus by nuclear localization signals
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