Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts

Stenhoff, Jonas; Dahlbäck, Björn; Hafizi, Sassan

doi:10.1016/j.bbrc.2004.05.070

Cited by 105 publications

(95 citation statements)

References 35 publications

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“…In the present study, we confirm that overexpression of MZF1 is tumorigenic, and for the first time, we report that MZF1 induces tumor growth and metastasis through the transactivation of Axl, thus adding to the molecular targets and mechanisms that can mediate an oncogenic potential of MZF1 in epithelialderived tissues. Axl has been reported as a transforming gene (21) that is overexpressed in several tumors (22)(23)(24)(25)(26)(27), and the Gas6/Axl signaling pathway is known to induce cell proliferation, antiapoptosis, migration, invasion, and angiogenic processes, which are most likely mediated through Ras, Src, mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/Akt, and NF-κB signaling pathways (14,15,19,29,31,32,(44)(45)(46)(47)(48)(49). However, still further studies are needed to enhance the understanding of the downstream components of the Gas6/Axl signaling axis in tumor formation.…”

Section: Discussionmentioning

confidence: 99%

“…Gas6 binds to TAM family members with different affinities. Gas6 was first discovered as an upregulated gene in growth-arrested cells (12), and further studies with Gas6 signaling suggested its role in cell survival (13,14), proliferation (15,16), stimulation of cell migration (17), and cell-cell adhesion through Axl (18). Intracellular signaling of Axl is also activated by its homophilic and heterophilic interactions (19), mediated mainly by a multisubstrate docking site (20).…”

Section: Introductionmentioning

confidence: 99%

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Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Mudduluru

Vajkoczy

Allgayer

2010

Molecular Cancer Research

118

129

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Myeloid zinc finger 1 (MZF1) is a member of the SCAN domain family transcription factors that form dimers through their highly conserved SCAN motifs. Silencing of MZF1 inhibits cell proliferation, and abnormal expression of MZF1 results in cancer development. However, a potential role of MZF1 in metastasis remains unclear. Axl is a receptor tyrosine kinase and was first identified as a transforming gene in chronic myeloid leukemia. Axl overexpression induces proliferation, migration, and invasion and is highly expressed in different human cancers. In this study, we show that overexpression of MZF1 induces migration and invasion in colorectal (Rko, SW480) and cervical (HeLa) cancer cells. In addition, we show that MZF1 binds to the Axl promoter, transactivates promoter activity, and enhances Axl-mRNA and protein expression in a dose-dependent manner. In vitro, sh-RNA knockdown of Axl reduced MZF1-induced migration and invasion in HeLa and Rko cells (P = 0.05). Additionally, Rko cells overexpressing MZF1 showed increased tumor formation and liver metastasis in the chicken-embryo-metastasis assay in vivo. Furthermore, the expression of MZF1 and Axl was significantly higher in resected colorectal tumors compared with corresponding normal tissues (P = 0.02; P = 0.05), and MZF1 expression was positively correlated with Axl gene expression in tumor tissues (P < 0.01). Taken together, this is the first study to show that MZF1 induces invasion and in vivo metastasis in colorectal and cervical cancer, at least in part by regulating Axl gene expression. Mol Cancer Res; 8(2); 159-69. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Mudduluru

Vajkoczy

Allgayer

2010

Molecular Cancer Research

118

129

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“…Overexpression of Axl can transform fibroblasts even in the absence of a ligand (Burchert et al, 1998). Axl is known to induce cell survival (Melaragno et al, 2004;van Ginkel et al, 2004), proliferation (Stenhoff et al, 2004;Sainaghi et al, 2005), stimulation of cell migration and cell-cell adhesion (McCloskey et al, 1997). Moreover, an increased expression of Axl is associated with invasion, metastasis, angiogenesis, and is found in metastatic colon, prostate carcinoma, gastric and endometrial cancers, breast cancers, lung cancers and sarcomas (Hafizi and Dahlback, 2006).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

et al. 2011

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Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 3 0 -UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 3 0 -UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre-miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung-or liver-metastases in a chorion-allantoicmembrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n ¼ 44), miR34a and miR-199a/b were found to be downregulated and significantly co-expressed. A lower expression of all three miRs was significantly associated with squamous histotypes, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR-199a/b, which are suppressed by promoter methylation in solid cancer cells.

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“…Gas6 supports haematopoietic stem cell growth 6 and promotes fibroblast and endothelial cell survival. [7][8][9] Gas6/Axl signaling induces accumulation of mesangial cells in kidney fibrosis, 10,11 vascular smooth muscle cells in response to intimal vascular injury, 12 and cardiac fibroblasts 9 during the wound healing process. Thus, this pathway has been increasingly implicated in growth and survival processes during development, regeneration, and tissue repair.…”

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confidence: 99%

Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

et al. 2006

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The protein product of the growth arrest-specific gene 6 (Gas6) is a secreted ligand for tyrosine kinase receptors, among which Axl is the most widely distributed and displays the highest affinity for Gas6. The Gas6/Axl signaling pathway has been increasingly implicated in growth and survival processes occurring during development and tissue repair. In liver, after an acute or chronic injury, repair involves macrophages and hepatic stellate cells (HSC) activated into myofibroblastic cells (HSC/MFB), which produce cytokines and matrix proteins. We investigated the expression and the role of Gas6 and its receptor Axl in liver repair. Three days after CCl 4 -induced liver injury in the rat, we detected the expression of Gas6 in ED1-positive macrophages as well as in desmin-positive HSC, which accumulated in injured areas. Axl, the high-affinity receptor for Gas6, was detected in macrophages, HSC, and HSC/MFB. In vitro, expression of ␥-carboxylated Gas6 was strongly induced in HSC along with their transformation into myofibroblasts, and it exerted an anti-apoptotic effect on both HSC and HSC/MFB mediated by the Axl/PI3-kinase/Akt pathway. In conclusion, Gas6 is a survival factor for these cells and we suggest

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Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts

Cited by 105 publications

References 35 publications

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

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Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts

Cited by 105 publications

References 35 publications

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

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Induction of Gas6 protein in CCl₄-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells