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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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Related in: MedlinePlus

Structural and functional features of the serine-rich domain of DLC-1. (A). Graphical representation of the predicted secondary structure of the human DLC-1 protein, performed using the FoldIndex program (http://bioportal.weizmann.ac.il/fldbin/findex). The serine-rich region between the SAM and RhoGAP domains is predicted to have a largely unfolded conformation. (B). Features of the serine-rich region. The amino acid sequence of the region between the SAM and RhoGAP domains (residues 79–638) of human DLC-1 is shown, and residues that were found to be phosphorylated in the mouse [51] and rat [49,50] DLC-1 proteins are indicated in yellow. Phosphorylation of Ser549 was presumed, since the equivalent serine in a highly conserved region of mouse DLC-2 was phosphorylated [51]. The tensin-binding site (SIYDNV) and the LD motif (LDDILYHV) are shown in blue.
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fig04: Structural and functional features of the serine-rich domain of DLC-1. (A). Graphical representation of the predicted secondary structure of the human DLC-1 protein, performed using the FoldIndex program (http://bioportal.weizmann.ac.il/fldbin/findex). The serine-rich region between the SAM and RhoGAP domains is predicted to have a largely unfolded conformation. (B). Features of the serine-rich region. The amino acid sequence of the region between the SAM and RhoGAP domains (residues 79–638) of human DLC-1 is shown, and residues that were found to be phosphorylated in the mouse [51] and rat [49,50] DLC-1 proteins are indicated in yellow. Phosphorylation of Ser549 was presumed, since the equivalent serine in a highly conserved region of mouse DLC-2 was phosphorylated [51]. The tensin-binding site (SIYDNV) and the LD motif (LDDILYHV) are shown in blue.

Mentions: Secondary structure analysis using the programs FoldIndex (http://bioportal.weizmann.ac.il/fldbin/findex) and PONDR (http://www.pondr.com) predicts that large stretches of the SR region are not likely to adopt a globular conformation (Fig. 4). Instead, this domain has several features in common with a class of proteins that have been termed intrinsically unstructured (or disordered) proteins [47, 48]. Unstructured protein domains are characteristically enriched in amino acids that promoter disorder (S, P, Q, E, K) and deficient in hydrophobic amino acids that form the core of globular proteins. Compared to globular domains, unstructured domains tend to have a lower degree of sequence conservation, due to a faster rate of evolution. This category includes many regulatory and signalling proteins, and their lack of secondary structure has been recognized as an important factor in the functions of these proteins. Their open, extended conformation confers flexibility and the ability to harbour multiple sites for interactions with other molecules. The unfolded structure can also impart increased susceptibility to proteolysis, providing a means for regulated turnover of the protein.


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)

Structural and functional features of the serine-rich domain of DLC-1. (A). Graphical representation of the predicted secondary structure of the human DLC-1 protein, performed using the FoldIndex program (http://bioportal.weizmann.ac.il/fldbin/findex). The serine-rich region between the SAM and RhoGAP domains is predicted to have a largely unfolded conformation. (B). Features of the serine-rich region. The amino acid sequence of the region between the SAM and RhoGAP domains (residues 79–638) of human DLC-1 is shown, and residues that were found to be phosphorylated in the mouse [51] and rat [49,50] DLC-1 proteins are indicated in yellow. Phosphorylation of Ser549 was presumed, since the equivalent serine in a highly conserved region of mouse DLC-2 was phosphorylated [51]. The tensin-binding site (SIYDNV) and the LD motif (LDDILYHV) are shown in blue.
© Copyright Policy
Related In: Results  -  Collection

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

fig04: Structural and functional features of the serine-rich domain of DLC-1. (A). Graphical representation of the predicted secondary structure of the human DLC-1 protein, performed using the FoldIndex program (http://bioportal.weizmann.ac.il/fldbin/findex). The serine-rich region between the SAM and RhoGAP domains is predicted to have a largely unfolded conformation. (B). Features of the serine-rich region. The amino acid sequence of the region between the SAM and RhoGAP domains (residues 79–638) of human DLC-1 is shown, and residues that were found to be phosphorylated in the mouse [51] and rat [49,50] DLC-1 proteins are indicated in yellow. Phosphorylation of Ser549 was presumed, since the equivalent serine in a highly conserved region of mouse DLC-2 was phosphorylated [51]. The tensin-binding site (SIYDNV) and the LD motif (LDDILYHV) are shown in blue.
Mentions: Secondary structure analysis using the programs FoldIndex (http://bioportal.weizmann.ac.il/fldbin/findex) and PONDR (http://www.pondr.com) predicts that large stretches of the SR region are not likely to adopt a globular conformation (Fig. 4). Instead, this domain has several features in common with a class of proteins that have been termed intrinsically unstructured (or disordered) proteins [47, 48]. Unstructured protein domains are characteristically enriched in amino acids that promoter disorder (S, P, Q, E, K) and deficient in hydrophobic amino acids that form the core of globular proteins. Compared to globular domains, unstructured domains tend to have a lower degree of sequence conservation, due to a faster rate of evolution. This category includes many regulatory and signalling proteins, and their lack of secondary structure has been recognized as an important factor in the functions of these proteins. Their open, extended conformation confers flexibility and the ability to harbour multiple sites for interactions with other molecules. The unfolded structure can also impart increased susceptibility to proteolysis, providing a means for regulated turnover of the protein.

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