ArticlePloS one2012
The role of Dlc1 isoform 2 in K-Ras2(G12D) induced thymic cancer.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 14 citations in OpenAlex.
- Loss of cholinergic receptor muscarinic 1 impairs cortical mitochondrial structure and function: implications in Alzheimer's disease.Frontiers in cell and developmental biology · 2023Article
- Functional antagonism between CagA and DLC1 in gastric cancer.Cell death discovery · 2022Article
- Thymic Epithelial Neoplasms: Focusing on the Epigenetic Alterations.International journal of molecular sciences · 2022Review
- Cancer-Associated Point Mutations in theCancer research · 2020Article
- RHO GTPases in cancer: known facts, open questions, and therapeutic challenges.Biochemical Society transactions · 2018Review
- Dlc1 interaction with non-muscle myosin heavy chain II-A (Myh9) and Rac1 activation.Biology open · 2016Article
- Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants.Oncotarget · 2016Article
- Rho, ROCK and actomyosin contractility in metastasis as drug targets.F1000Research · 2016Review
- Crossing the endothelial barrier during metastasis.Nature reviews. Cancer · 2013Review
- Inactivation of the Dlc1 gene cooperates with downregulation of p15INK4b and p16Ink4a, leading to neoplastic transformation and poor prognosis in human cancer.Cancer research · 2012Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Deleted in liver cancer one (Dlc1) tumor suppressor gene encodes a RhoGTPase activating protein (RhoGAP). The Dlc1 gene has multiple transcriptional isoforms and we have previously established a mouse strain containing a gene trap (gt) insertion, which specifically reduces the expression of the 6.1 kb isoform (isoform 2). This gene trapped allele when homozygous results in embryonic lethality and the heterozygous gene trapped mice do not show an increased incidence of cancers, suggesting that cooperating oncogenic changes may be required for transformation. In the present work, we have studied the in vivo cooperation between oncogenic K-Ras2 and Dlc1 genes in tumourigenesis. We have observed an increase in invasive thymic cancers, including both thymomas and lymphomas, resulting in significantly shortened life spans in mice heterozygous for the gt Dlc1 allele and an inducible LSL-K-Ras2(G12D) allele compared with the LSL-K-Ras2(G12D) only mice. The heterozygous mice showed a high degree of metastasis in the lung. We have found tumour specific selective hypermethylation of the Dlc1 isoform 2 promoter and reduction of the corresponding protein expression in thymic lymphoma (TL) and thymic epithelial carcinoma (TEC) derived from the thymic tumours. The Dlc1 deficient thymic lymphoma cell lines exhibited increased trans-endothelial cell migration. TEC cell lines also exhibited increased stress fiber formation and Rho activity. Introduction of the three Dlc1 isoforms tagged with GFP into these cells resulted in different morphological changes. These results suggest that loss of expression of only isoform 2 may be sufficient for the development of thymic tumors and metastasis.
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