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[hepatoma-derived growth factor] also abbr. HDGF (which is the approved gene symbol for the human gene; not identical with bFGF, which was also named HDGF in earlier publications). This factor of approximately 64 kDa is found in the conditioned medium of a human hepatoma cell line, HuH-7, established from hepatoma tissue of an adult male (Nakamura et al, 1989).

Cloning of HDGF reveals a cDNA encoding a heparin binding protein of 240 amino acids (see also: HBGF). HDGF shares homology with the high mobility group HMG-1 protein but does not contain a HMG box motif (Nakamura et al, 1994). Due to this sequence relationship the factor is being referred to also as HMG1L2 [high mobility group protein 1-like-2].

The human gene has been mapped to chromosome Xq25 (Wanschura et al, 1996).

The mouse counterpart of the protein and two HDGF-related proteins (HDGF-related protein-1 (HRP-1), and HDGF-related protein-2 (HRP-2; also: HDGFRP2 [Hepatoma-derived growth factor-related protein 2]) have been cloned (Izumoto et al, 1997). The proteins have a highly conserved 98 amino acid sequence at the amino terminus. HRP-1 and HRP-2 proteins are 46 and 432 amino acids longer than mouse HDGF, respectively, and have no conserved amino acid sequence other than the aminoterminal region. All proteins contain a putative nuclear localization sequence (see: signal sequence). HRP-1 is expressed specifically in testis (Kuroda et al, 1999. Mouse HDGF and HRP-2 are expressed predominantly in testis and skeletal muscle but also in a variety of other tissues (Izumoto et al, 1997).

Another HDGF-related protein of 203 amino acids, HDGF-related protein-3 (HRP-3; also: HDGFRP3 [Hepatoma-derived growth factor-related protein 3]), does not contain a signal sequence for secretion. HRP-3 contains a nuclear localizing signal (NLS) sequence, HRP-3 is expressed predominantly in the testis and brain and to a lesser degree in the heart, ovaries, kidneys, spleen, and liver in humans. The HRP-3 gene maps to human chromosome 15q25 (Ikegame et al, 1999). HDGF is present in the mouse brain from the embryonic period until adulthood and is expressed mainly in neurons. HDGF has a neurotrophic effect and can partially prevent the cell death of neurons in which endogenous HDGF expression is suppressed (Zhou et al, 2004). Soluble HRP-3 acts as a neurotrophic factor for cultured primary cortical neurons. Antibody-mediated neutralization of HRP-3 function results in neuronal degeneration. HRP-3 acts as a survival factor for cultured neurons in culture and promotes neurite outgrowth when it is presented as a coated substrate but not as a soluble factor (Abouzied MM et al, 2010).

The cDNA of bovine HRP-4 (Dietz et al, 2002) encodes a small acidic protein of 235 amino acids. The gene appears to be expressed in a testes-specific manner. HRP-4 is mitogenic for cultured primary human fibroblasts in serum-free medium.

A comparison of the HRP-1, HRP-2, HRP-3, HRP-4 sequences with the sequence of LEDGF (lens epithelium-derived growth factor) shows that these proteins share a conserved N-terminal part of 91 amino acids but have C-termini of different lengths and charge.

HDGF functions as an autocrine growth factor for HuH-7 hepatoma cells, which grow autonomously in a serum-free chemically defined medium. Growth is blocked by the protein kinase C inhibitor H7 (Kambe et al, 2000). Kishima et al (2002) have reported that HDGF is one of important autocrine and/or intracrine factors for hepatoma cells. Antisense oligonucleotides of HDGF can suppress the proliferation of hepatoma cells. Enomoto et al (2002) have reported that HDGF is highly expressed in developing liver and promotes fetal hepatocyte proliferation.

Everett et al (2004) have reported that HDGF is expressed in endothelial cells of fetal lung and small mature arteries and veins. Exogenous recombinant HDGF significantly stimulates blood vessel formation in the chorioallantoic membrane assay, a biologic assay for angiogenesis. Okuda et al (2003) have reported that HDGF induces tumorigenesis in vivo through both direct angiogenic activity and induction of VEGF.

HDGF mRNA is expressed in proliferating smooth muscle cells after serum stimulation. HDGF stimulates smooth muscle cell growth and may thus be a factor regulating cell growth during development and in response to vascular injury (Everett et al, 2000). Everett et al (2001) have reported that nuclear targeting is required for the stimulation of mitogenesis by HDGF in vascular smooth muscle cells. Oliver and Al-Awqati (1998) have shown that rat HDGF is an endothelial mitogen that is present in embryonic kidney. Its expression is synchronous with nephrogenesis. Rat HDGF is expressed highly in the fetal conotruncus, heart, kidney, brain, and gut (Everett, 2001).

Matsuyama et al (2001) have reported that the expression of HDGF is reduced in established radioresistant cells, and its reduction is associated with reduced sensitivity to irradiation in esophageal cancer. HDGF plays an important role in the development or progression of hepatocellular carcinomas in humans and rodents (Yoshida et al, 2003). Hu et al (2003) have reported that the increased expression of HDGF is correlated with the proliferating states of hepatocellular carcinomas and represents a prognostic factor for patients after surgery.

Nakamura et al (2002) have reported that HDGF plays an important role in epithelial cell renewal of intestinal crypts as a growth and survival factor, and that autoantibody against HDGF may delay mucosal healing and repair by inhibiting the stimulatory effects of HDGF on epithelial cell proliferation, resulting in a chronic process of colonic mucosal injury.

Mori et al (2002) have reported that HDGF is involved in lung remodeling by stimulating epithelial growth. Bernard et al (2003) have reported that HDGF is one of the genes strongly expressed during melanoma progression. HDGF is a prognostic marker for non small cell lung cancer, with patients having showing high HDGF levels having a poor prognosis (Iwasaki et al, 2004; Ren et al, 2004)

Machuy et al (2005) have reported that silencing of HuHGF expression by small interfering RNAs inhibits cell death by apoptosis. HuHGF is required for the release of pro-apoptotic factors induced by TNF-alpha.

Lin et al (2008) have identified HDGF as a chemotactic factor for bone marrow-derived mesenchymal stromal cells, which are known to localize to solid tumors.

For other entries pertaining to cell death mechanisms see also the Apoptosis and Cell Death Dictionary section of this encyclopedia.

Copyright 2012 by H IBELGAUFTS. All rights reserved.


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