Ets-domain transcription factor Ets21c and nuclear receptor Ftz-F1 are novel effectors of JNK promoting tumor malignancy

ABSTRACT: Cancer represents a complex family of diseases, characterized by the uncontrolled malignant growth of a particular cell type and by metastatic dissemination of these transformed cells to secondary sites. The hallmark tumor features emerge as a result of aberrant cellular signaling and pathological gene expression driven by cooperating genetic lesions. Being the convergence points of signaling pathways, transcription factors play crucial roles in cancer. Here, we define a transcription factor network that triggers an abnormal gene expression program promoting malignancy of clonal tumors, generated in Drosophila imaginal disc epithelium by overexpressing oncogenic Ras (RasV12) in a background lacking the tumor suppressor gene scribble (scrib1). We show that the nuclear receptor Ftz-F1 and the ETS-domain transcription factor Ets21c are upregulated in the rasV12scrib1 tumors in response to activated Jun-N-terminal kinase (JNK) signaling. Depletion of either Ftz-F1 or Ets21c improves viability of Drosophila larvae suffering from tumors, and this effect can be further enhanced by simultaneous removal of the Jun-dimerizing partner Fos. We identified Fos as a key mediator of JNK-induced differentiation defects and further show that Ftz-F1 and Fos are required for tumor invasiveness. However, only Ets21c can efficiently substitute for JNK and cooperate with RasV12 to induce invasive tumors that recapitulate hallmarks of malignant rasV12scrib1 tumors including elevated matrix metalloprotease (MMP1) and insulin-like peptide 8 (Dilp8) expression. In conclusion, our study provides functional evidence for a network of cooperating transcription factor that dictates target gene expression and promotes tumor phenotypes in response to aberrant JNK signaling. 20 samples analyzed, 4 control samples

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Mirka Uhlirova 

PROVIDER: E-GEOD-65261 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress