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DLC-1:a Rho GTPase-activating protein and tumour suppressor.

Durkin ME, Yuan BZ, Zhou X, Zimonjic DB, Lowy DR, Thorgeirsson SS, Popescu NC - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: Since its discovery, compelling evidence has accumulated that demonstrates a role for DLC-1 as a bona fide tumour suppressor gene in different types of human cancer.Loss of DLC-1 expression mediated by genetic and epigenetic mechanisms has been associated with the development of many human cancers, and restoration of DLC-1 expression inhibited the growth of tumour cells in vivo and in vitro.Two closely related genes, DLC-2 and DLC-3, may also be tumour suppressors.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

ABSTRACT
The deleted in liver cancer 1 (DLC-1) gene encodes a GTPase activating protein that acts as a negative regulator of the Rho family of small GTPases. Rho proteins transduce signals that influence cell morphology and physiology, and their aberrant up-regulation is a key factor in the neoplastic process, including metastasis. Since its discovery, compelling evidence has accumulated that demonstrates a role for DLC-1 as a bona fide tumour suppressor gene in different types of human cancer. Loss of DLC-1 expression mediated by genetic and epigenetic mechanisms has been associated with the development of many human cancers, and restoration of DLC-1 expression inhibited the growth of tumour cells in vivo and in vitro. Two closely related genes, DLC-2 and DLC-3, may also be tumour suppressors. This review presents the current status of progress in understanding the biological functions of DLC-1 and its relatives and their roles in neoplasia.

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Tumour suppressor activity of DLC1. (A) The human DLC-1 gene is located in band 8p22, a chromosomal region of DNA copy-number losses in a number of cancers, as demonstrated by conventional (left) and array-based (right) comparative genom-ic hybridization. Re-expression of the DLC-1 cDNA in human tumour cells that lack expression of the endogenous gene results in suppression of colony formation (B), suppression of cell invasion (C), reduction of actin stress fibres (D), diminution of vin-culin-containing focal adhesions (E), reduction of tumour size in nude mice (F), induction of apoptosis (as demonstrated by cell accumulation of sub-G1 phase and chromatin fragmentation) (G), and suppression of formation of lung metastases in nude mice (H). In each pair of photographs, DLC-1-expressing cells are below (C, D, E, H) or to the right (B, F) of cells transfected with control vectors. Images in H are reproduced with permission from Cancer Research.
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fig01: Tumour suppressor activity of DLC1. (A) The human DLC-1 gene is located in band 8p22, a chromosomal region of DNA copy-number losses in a number of cancers, as demonstrated by conventional (left) and array-based (right) comparative genom-ic hybridization. Re-expression of the DLC-1 cDNA in human tumour cells that lack expression of the endogenous gene results in suppression of colony formation (B), suppression of cell invasion (C), reduction of actin stress fibres (D), diminution of vin-culin-containing focal adhesions (E), reduction of tumour size in nude mice (F), induction of apoptosis (as demonstrated by cell accumulation of sub-G1 phase and chromatin fragmentation) (G), and suppression of formation of lung metastases in nude mice (H). In each pair of photographs, DLC-1-expressing cells are below (C, D, E, H) or to the right (B, F) of cells transfected with control vectors. Images in H are reproduced with permission from Cancer Research.

Mentions: The DLC-1 gene was identified by Yuan and colleagues as a genomic DNA segment under-represented in a human hepatocellular carcinoma (HCC) specimen, using representational difference analysis, a PCR-based subtractive hybridization technique [16]. The DLC-1 locus was mapped to the human chromosome 8p22 region frequently lost in HCC and other cancers (Fig. 1A), and it was named ‘deleted in liver cancer’ when found to be deleted in primary HCC and HCC cell lines [16]. Sequencing of the DLC-1 cDNA showed that it was the human orthologue of the rat p122RhoGAP protein, which had been cloned by Homma and Emori when screening a >11 expression library with anti-serum against phospholipase δ 1 (PLCδ 1) [17]. The predicted amino acid sequence of p122RhoGAP/DLC-1 contains a RhoGAP domain, a conserved region of around 200 amino acids responsible for the catalytic activity of RhoGAPs [10]. Further analysis of the DLC-1 polypeptide sequence revealed the presence of two additional conserved elements, an N-terminal sterile alpha motif (SAM) domain and a C-terminal steroidogenic acute regulatory protein (StAR)-related lipid-transfer (START) domain [18].


DLC-1:a Rho GTPase-activating protein and tumour suppressor.

Durkin ME, Yuan BZ, Zhou X, Zimonjic DB, Lowy DR, Thorgeirsson SS, Popescu NC - J. Cell. Mol. Med. (2007 Sep-Oct)

Tumour suppressor activity of DLC1. (A) The human DLC-1 gene is located in band 8p22, a chromosomal region of DNA copy-number losses in a number of cancers, as demonstrated by conventional (left) and array-based (right) comparative genom-ic hybridization. Re-expression of the DLC-1 cDNA in human tumour cells that lack expression of the endogenous gene results in suppression of colony formation (B), suppression of cell invasion (C), reduction of actin stress fibres (D), diminution of vin-culin-containing focal adhesions (E), reduction of tumour size in nude mice (F), induction of apoptosis (as demonstrated by cell accumulation of sub-G1 phase and chromatin fragmentation) (G), and suppression of formation of lung metastases in nude mice (H). In each pair of photographs, DLC-1-expressing cells are below (C, D, E, H) or to the right (B, F) of cells transfected with control vectors. Images in H are reproduced with permission from Cancer Research.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401278&req=5

fig01: Tumour suppressor activity of DLC1. (A) The human DLC-1 gene is located in band 8p22, a chromosomal region of DNA copy-number losses in a number of cancers, as demonstrated by conventional (left) and array-based (right) comparative genom-ic hybridization. Re-expression of the DLC-1 cDNA in human tumour cells that lack expression of the endogenous gene results in suppression of colony formation (B), suppression of cell invasion (C), reduction of actin stress fibres (D), diminution of vin-culin-containing focal adhesions (E), reduction of tumour size in nude mice (F), induction of apoptosis (as demonstrated by cell accumulation of sub-G1 phase and chromatin fragmentation) (G), and suppression of formation of lung metastases in nude mice (H). In each pair of photographs, DLC-1-expressing cells are below (C, D, E, H) or to the right (B, F) of cells transfected with control vectors. Images in H are reproduced with permission from Cancer Research.
Mentions: The DLC-1 gene was identified by Yuan and colleagues as a genomic DNA segment under-represented in a human hepatocellular carcinoma (HCC) specimen, using representational difference analysis, a PCR-based subtractive hybridization technique [16]. The DLC-1 locus was mapped to the human chromosome 8p22 region frequently lost in HCC and other cancers (Fig. 1A), and it was named ‘deleted in liver cancer’ when found to be deleted in primary HCC and HCC cell lines [16]. Sequencing of the DLC-1 cDNA showed that it was the human orthologue of the rat p122RhoGAP protein, which had been cloned by Homma and Emori when screening a >11 expression library with anti-serum against phospholipase δ 1 (PLCδ 1) [17]. The predicted amino acid sequence of p122RhoGAP/DLC-1 contains a RhoGAP domain, a conserved region of around 200 amino acids responsible for the catalytic activity of RhoGAPs [10]. Further analysis of the DLC-1 polypeptide sequence revealed the presence of two additional conserved elements, an N-terminal sterile alpha motif (SAM) domain and a C-terminal steroidogenic acute regulatory protein (StAR)-related lipid-transfer (START) domain [18].

Bottom Line: Since its discovery, compelling evidence has accumulated that demonstrates a role for DLC-1 as a bona fide tumour suppressor gene in different types of human cancer.Loss of DLC-1 expression mediated by genetic and epigenetic mechanisms has been associated with the development of many human cancers, and restoration of DLC-1 expression inhibited the growth of tumour cells in vivo and in vitro.Two closely related genes, DLC-2 and DLC-3, may also be tumour suppressors.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

ABSTRACT
The deleted in liver cancer 1 (DLC-1) gene encodes a GTPase activating protein that acts as a negative regulator of the Rho family of small GTPases. Rho proteins transduce signals that influence cell morphology and physiology, and their aberrant up-regulation is a key factor in the neoplastic process, including metastasis. Since its discovery, compelling evidence has accumulated that demonstrates a role for DLC-1 as a bona fide tumour suppressor gene in different types of human cancer. Loss of DLC-1 expression mediated by genetic and epigenetic mechanisms has been associated with the development of many human cancers, and restoration of DLC-1 expression inhibited the growth of tumour cells in vivo and in vitro. Two closely related genes, DLC-2 and DLC-3, may also be tumour suppressors. This review presents the current status of progress in understanding the biological functions of DLC-1 and its relatives and their roles in neoplasia.

Show MeSH
Related in: MedlinePlus