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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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Co-localization of DLC-1 and tensin. Confocal photomicrographs showing endogenous tensin (red, A) and transfected GFP-DLC1 fusion protein (green, B) in human fibroblasts. The merged image (C) shows co-localization of tensin and DLC-1 in focal adhesions, indicated in yellow. The bar represents 10 μm. (Images courtesy of Dr. Guorong Li, Laboratory of Cellular Oncology, National Cancer Institute).
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fig05: Co-localization of DLC-1 and tensin. Confocal photomicrographs showing endogenous tensin (red, A) and transfected GFP-DLC1 fusion protein (green, B) in human fibroblasts. The merged image (C) shows co-localization of tensin and DLC-1 in focal adhesions, indicated in yellow. The bar represents 10 μm. (Images courtesy of Dr. Guorong Li, Laboratory of Cellular Oncology, National Cancer Institute).

Mentions: While DLC-1 ectopically expressed in cultured cells can have a diffuse cytoplasmic localization [39, 55, 57], in certain cell types DLC-1 may be present in focal adhesions. In normal rat kidney (NRK) fibroblasts, endogenous p122 RhoGAP/DLC-1 and a GFP-tagged N-terminal fragment (aa 1–534) were detected in focal adhesions, as shown by their co-localization with the tips of actin stress fibres and with vin-culin, a focal adhesion protein [58]. Recently, yeast two-hybrid screenings identified DLC-1 as a binding partner for members of the tensin family of focal adhesion proteins [41, 59, 60]. The four tensin proteins (tensin1, tensin2, tensin3 and cten) bind to the cytoplasmic tails of β integrins [61]. The middle region of DLC1 was found to interact with the C-ter-mini of the tensins, which consist of SH2 (src homology 2) and phosphotyrosine-binding (PTB) domains [41, 59, 60]. DLC-1 bound to the SH2 domains of cten and tensin1, and the binding site was mapped to aa 440–445 (SIYDNV) of DLC-1 [41, 60]. Mutation of Tyr442 of DLC-1 abolished the SH2 domain binding, but phosphorylation of Tyr442 was not required for the interaction, unlike most ligands for SH2 domains. [41, 60]. Binding of DLC-1 to the PTB domains of tensin1 and tensin2 was also detected [41, 59], and DLC-1 competed with integrin β3 for binding to the tensin1 PTB domain [41]. Tensin and DLC-1 co-localize (Fig. 5), and the localization of ectopically expressed DLC-1 to focal adhesion-like structures was dependent on the co-expression of tensin proteins [41, 59, 60].


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)

Co-localization of DLC-1 and tensin. Confocal photomicrographs showing endogenous tensin (red, A) and transfected GFP-DLC1 fusion protein (green, B) in human fibroblasts. The merged image (C) shows co-localization of tensin and DLC-1 in focal adhesions, indicated in yellow. The bar represents 10 μm. (Images courtesy of Dr. Guorong Li, Laboratory of Cellular Oncology, National Cancer Institute).
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Related In: Results  -  Collection

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

fig05: Co-localization of DLC-1 and tensin. Confocal photomicrographs showing endogenous tensin (red, A) and transfected GFP-DLC1 fusion protein (green, B) in human fibroblasts. The merged image (C) shows co-localization of tensin and DLC-1 in focal adhesions, indicated in yellow. The bar represents 10 μm. (Images courtesy of Dr. Guorong Li, Laboratory of Cellular Oncology, National Cancer Institute).
Mentions: While DLC-1 ectopically expressed in cultured cells can have a diffuse cytoplasmic localization [39, 55, 57], in certain cell types DLC-1 may be present in focal adhesions. In normal rat kidney (NRK) fibroblasts, endogenous p122 RhoGAP/DLC-1 and a GFP-tagged N-terminal fragment (aa 1–534) were detected in focal adhesions, as shown by their co-localization with the tips of actin stress fibres and with vin-culin, a focal adhesion protein [58]. Recently, yeast two-hybrid screenings identified DLC-1 as a binding partner for members of the tensin family of focal adhesion proteins [41, 59, 60]. The four tensin proteins (tensin1, tensin2, tensin3 and cten) bind to the cytoplasmic tails of β integrins [61]. The middle region of DLC1 was found to interact with the C-ter-mini of the tensins, which consist of SH2 (src homology 2) and phosphotyrosine-binding (PTB) domains [41, 59, 60]. DLC-1 bound to the SH2 domains of cten and tensin1, and the binding site was mapped to aa 440–445 (SIYDNV) of DLC-1 [41, 60]. Mutation of Tyr442 of DLC-1 abolished the SH2 domain binding, but phosphorylation of Tyr442 was not required for the interaction, unlike most ligands for SH2 domains. [41, 60]. Binding of DLC-1 to the PTB domains of tensin1 and tensin2 was also detected [41, 59], and DLC-1 competed with integrin β3 for binding to the tensin1 PTB domain [41]. Tensin and DLC-1 co-localize (Fig. 5), and the localization of ectopically expressed DLC-1 to focal adhesion-like structures was dependent on the co-expression of tensin proteins [41, 59, 60].

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