Kuelshammer, Eva, Mundorf, Juliane, Kilinc, Merve, Frommolt, Peter ORCID: 0000-0002-1966-8014, Wagle, Prerana and Uhlirova, Mirka ORCID: 0000-0002-5735-8287 (2015). Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy. Dis. Model. Mech., 8 (10). S. 1279 - 1294. CAMBRIDGE: COMPANY BIOLOGISTS LTD. ISSN 1754-8411

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Abstract

Cancer initiation and maintenance of the transformed cell state depend on altered cellular signaling and aberrant activities of transcription factors (TFs) that drive pathological gene expression in response to cooperating genetic lesions. Deciphering the roles of interacting TFs is therefore central to understanding carcinogenesis and for designing cancer therapies. Here, we use an unbiased genomic approach to define a TF network that triggers an abnormal gene expression program promoting malignancy of clonal tumors, generated in Drosophila imaginal disc epithelium by gain of oncogenic Ras (Ras(V12)) and loss of the tumor suppressor Scribble (scrib(1)). We show that malignant transformation of the ras(V12)scrib(1) tumors requires TFs of distinct families, namely the bZIP protein Fos, the ETS-domain factor Ets21c and the nuclear receptor Ftz-F1, all acting downstream of Jun-N-terminal kinase (JNK). Depleting any of the three TFs improves viability of tumor-bearing larvae, and this positive effect can be enhanced further by their combined removal. Although both Fos and Ftz-F1 synergistically contribute to ras(V12)scrib(1) tumor invasiveness, only Fos is required for JNK-induced differentiation defects and Matrix metalloprotease (MMP1) upregulation. In contrast, the Fos-dimerizing partner Jun is dispensable for JNK to exert its effects in rasV12scrib1 tumors. Interestingly, Ets21c and Ftz-F1 are transcriptionally induced in these tumors in a JNK- and Fos-dependent manner, thereby demonstrating a hierarchy within the tripartite TF network, with Fos acting as the most upstream JNK effector. Of the three TFs, only Ets21c can efficiently substitute for loss of polarity and cooperate with RasV12 in inducing malignant clones that, like ras(V12)scrib(1) tumors, invade other tissues and overexpress MMP1 and the Drosophila insulin-like peptide 8 (Dilp8). While ras(V12)ets21c tumors require JNK for invasiveness, the JNK activity is dispensable for their growth. In conclusion, our study delineates both unique and overlapping functions of distinct TFs that cooperatively promote aberrant expression of target genes, leading to malignant tumor phenotypes.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kuelshammer, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mundorf, JulianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kilinc, MerveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frommolt, PeterUNSPECIFIEDorcid.org/0000-0002-1966-8014UNSPECIFIED
Wagle, PreranaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhlirova, MirkaUNSPECIFIEDorcid.org/0000-0002-5735-8287UNSPECIFIED
URN: urn:nbn:de:hbz:38-390955
DOI: 10.1242/dmm.020719
Journal or Publication Title: Dis. Model. Mech.
Volume: 8
Number: 10
Page Range: S. 1279 - 1294
Date: 2015
Publisher: COMPANY BIOLOGISTS LTD
Place of Publication: CAMBRIDGE
ISSN: 1754-8411
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LIVER RECEPTOR HOMOLOG-1; PROSTATE-CANCER; STEROIDOGENIC FACTOR-1; FUNCTIONAL-ANALYSIS; CELL-PROLIFERATION; ONCOGENIC RAS; AP-1 ACTIVITY; EXPRESSION; PROTEIN; GENEMultiple languages
Cell Biology; PathologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/39095

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