Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

Goruppi, Sandro; Ruaro, Elisabetta; Varnum, Brian; Schneider, Claudio

doi:10.1038/sj.onc.1202788

Cited by 127 publications

(150 citation statements)

References 81 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%

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%

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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“…Surprisingly, however, the Axl ligand, GAS-6, is only a weak mitogen in a restricted range of tissue such as 3T3, Schwann, and vascular smooth muscle cells (Goruppi et al, 1996;Gasic et al, 1992;Li et al, 1996) and appears to play a greater role in modulating cellular responses to other factors such as thrombin and angiotensin II (Nakano et al, 1995). That a ligand shows little mitogenic activity when interacting with a RTK with transforming function has been seen in the Eph receptor tyrosine kinase family (Brambilla et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Determinants for transformation induced by the Axl receptor tyrosine kinase

et al. 1998

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The Axl receptor tyrosine kinase is a transforming oncogene in NIH3T3 cells. In order to de®ne structural requirements of the Axl receptor necessary for transformation we passaged recombinant retroviruses carrying the axl cDNA in NIH3T3 cells, generating randomly mutated axl variants. Using this strategy, we have isolated three axl viral strains (1B1, SV8, and FFa4) that show augmented 3T3 cell transforming capacity associated with elevated p140 Axl . Upon sequencing, the 1B1 and SV8 proviruses possessed only silent mutations, making p140 Axl overexpression the most likely explanation for their increased transformation activity. However, the characterization of FFa4 revealed a deletion of sequences encoding the carboxy-terminal 45 amino acids leading to the generation of a chimeric transcript comprised of a truncated Axl receptor with a segment of the 3' UTR region. Mutational analysis revealed that the transforming activity of FFa4 was speci®c to the formation of the chimeric receptor rather than to the carboxyl-terminal truncation. Intriguingly, none of the viral strains were able to transform the murine cell lines NR-6 and 32D despite equivalent expression of surface p140 Axl protein. Further analysis showed that Axl's transforming potential is dependent on the host cell type, the presence of a putative pp190 as a facilitator for transformation, and the level of p140 Axl expression. Taken together, these results underscore the complexity of Axl biology which is dependent on receptor stoichiometry and the cellular background.

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“…The protein structure of the axl family is characterized by an extracellular domain with two immunoglobulin-like domains followed by two ®bro-nectin type III repeats and a cytoplasmic domain with intrinsic kinase activity (O'Bryan et al, 1991). AxlGas6 signaling activates the kinases Erk and Akt (Goruppi et al, 1997). The Axl-Gas6 interaction modulates multiple biological functions, including cell cycle reentry and prevention of cell death under serumstarved conditions (Goruppi et al, 1996(Goruppi et al, , 1997Bellosta et al, 1997), cell-to-cell adhesion (Bellosta et al, 1995), and chemotaxis (Fridell et al, 1998), which are attributed to the protein structures and signal transduction of both Gas6 and Axl.…”

Section: Introductionmentioning

confidence: 99%

Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis

et al. 2002

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Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

Cited by 127 publications

References 81 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

Determinants for transformation induced by the Axl receptor tyrosine kinase

Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis

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