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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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Origin of human DLC-1 and DLC-2 transcriptional variants. (A). Diagram of the genomic region at the 5′ end of DLC1, with exons represented by boxes. The five exons comprising the novel 5′sequence of the KIAA1723 transcript are labelled A–E, and the alternative first exon of the AK025544 transcript is denoted as 1*. The three transcripts share exons 2–14, and the distances between the putative transcription start sites (marked with arrows) and exon 2 are indicated. (B). Diagram of the 5’end of the DLC-2 gene, showing the first exons of the DLC-2α (1α), DLC-2β (1β) and DLC-2γ (1γ) isoforms. Exons 2–14 are common to all three transcripts, and the distances between exon 2 and the putative transcription start sites are indicated. The genomic DNA distances in A and B were obtained from the human genome sequence compilation (NCBI Build 36) and are not drawn to scale. The structures of the human DLC-3 gene and its transcripts were described in Ref 22.
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fig03: Origin of human DLC-1 and DLC-2 transcriptional variants. (A). Diagram of the genomic region at the 5′ end of DLC1, with exons represented by boxes. The five exons comprising the novel 5′sequence of the KIAA1723 transcript are labelled A–E, and the alternative first exon of the AK025544 transcript is denoted as 1*. The three transcripts share exons 2–14, and the distances between the putative transcription start sites (marked with arrows) and exon 2 are indicated. (B). Diagram of the 5’end of the DLC-2 gene, showing the first exons of the DLC-2α (1α), DLC-2β (1β) and DLC-2γ (1γ) isoforms. Exons 2–14 are common to all three transcripts, and the distances between exon 2 and the putative transcription start sites are indicated. The genomic DNA distances in A and B were obtained from the human genome sequence compilation (NCBI Build 36) and are not drawn to scale. The structures of the human DLC-3 gene and its transcripts were described in Ref 22.

Mentions: Several variant transcripts are associated with the DLC1 locus (Table 1 and Fig. 3A). The 7.4 kb KIAA1723 cDNA clone was isolated from a human hippocampus library and has the potential to encode a larger DLC-1 isoform of 1528 aa [26]. The KIAA1723 cDNA contains exons 2–14 of DLC1, but exon 1 is replaced by a novel 1.7 kb sequence, distributed on 5 exons upstream of the start of the major transcript. The putative promoter region of KIAA1723 is approx.400 kb upstream of exon 2, and there are also shorter transcripts originating from this promoter that would not encode a DLC-1-related protein (NM_024767). The existence of a larger DLC-1 polypeptide has not yet been verified experimentally. The second alternative transcript contains a novel first exon located 160 kb upstream of exon 2 and was cloned from HepG2 hepatoblastoma cells, where it seems to be enriched, based on the number of promoter tags in the Fantom database isolated from these cells (http://fantom.gsc.riken.go.jp). The HepG2-enriched first exon would substitute 47 aa for the first 13 aa of DLC-1. As a transcript with a similar 5' end was identified in the mouse, this DLC-1 iso-form may be functionally conserved.


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)

Origin of human DLC-1 and DLC-2 transcriptional variants. (A). Diagram of the genomic region at the 5′ end of DLC1, with exons represented by boxes. The five exons comprising the novel 5′sequence of the KIAA1723 transcript are labelled A–E, and the alternative first exon of the AK025544 transcript is denoted as 1*. The three transcripts share exons 2–14, and the distances between the putative transcription start sites (marked with arrows) and exon 2 are indicated. (B). Diagram of the 5’end of the DLC-2 gene, showing the first exons of the DLC-2α (1α), DLC-2β (1β) and DLC-2γ (1γ) isoforms. Exons 2–14 are common to all three transcripts, and the distances between exon 2 and the putative transcription start sites are indicated. The genomic DNA distances in A and B were obtained from the human genome sequence compilation (NCBI Build 36) and are not drawn to scale. The structures of the human DLC-3 gene and its transcripts were described in Ref 22.
© Copyright Policy
Related In: Results  -  Collection

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

fig03: Origin of human DLC-1 and DLC-2 transcriptional variants. (A). Diagram of the genomic region at the 5′ end of DLC1, with exons represented by boxes. The five exons comprising the novel 5′sequence of the KIAA1723 transcript are labelled A–E, and the alternative first exon of the AK025544 transcript is denoted as 1*. The three transcripts share exons 2–14, and the distances between the putative transcription start sites (marked with arrows) and exon 2 are indicated. (B). Diagram of the 5’end of the DLC-2 gene, showing the first exons of the DLC-2α (1α), DLC-2β (1β) and DLC-2γ (1γ) isoforms. Exons 2–14 are common to all three transcripts, and the distances between exon 2 and the putative transcription start sites are indicated. The genomic DNA distances in A and B were obtained from the human genome sequence compilation (NCBI Build 36) and are not drawn to scale. The structures of the human DLC-3 gene and its transcripts were described in Ref 22.
Mentions: Several variant transcripts are associated with the DLC1 locus (Table 1 and Fig. 3A). The 7.4 kb KIAA1723 cDNA clone was isolated from a human hippocampus library and has the potential to encode a larger DLC-1 isoform of 1528 aa [26]. The KIAA1723 cDNA contains exons 2–14 of DLC1, but exon 1 is replaced by a novel 1.7 kb sequence, distributed on 5 exons upstream of the start of the major transcript. The putative promoter region of KIAA1723 is approx.400 kb upstream of exon 2, and there are also shorter transcripts originating from this promoter that would not encode a DLC-1-related protein (NM_024767). The existence of a larger DLC-1 polypeptide has not yet been verified experimentally. The second alternative transcript contains a novel first exon located 160 kb upstream of exon 2 and was cloned from HepG2 hepatoblastoma cells, where it seems to be enriched, based on the number of promoter tags in the Fantom database isolated from these cells (http://fantom.gsc.riken.go.jp). The HepG2-enriched first exon would substitute 47 aa for the first 13 aa of DLC-1. As a transcript with a similar 5' end was identified in the mouse, this DLC-1 iso-form may be functionally conserved.

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