The CCL6 chemokine is differentially regulated by c-Myc and L-Myc, and promotes tumorigenesis and metastasis.
The CCL6 chemokine gene was identified as a direct positive target of the L-Myc oncoprotein in interleukin 3-dependent 32D myeloid cells. A mutant form of c-Myc, lacking a region of the NH(2)-terminal domain necessary for transcriptional repression (c-MycDeltaMBII), also up-regulated CCL6. Chromatin immunoprecipitation showed that L-Myc, c-MycDeltaMBII, and full-length c-Myc all bound the CCL6 promoter, although the latter was inactive in transcriptional up-regulation. Exogenously added CCL6 induced marked apoptosis in some cell types. However, in 32D cells, the coexpression of c-Myc and CCL6 abrogated interleukin 3 dependence and produced a highly leukemogenic phenotype. In two solid tumor models, CCL6 overexpression also accelerated tumor growth, and/or enhanced local and metastatic spread in association with marked apoptosis of the tumor capsule and adjacent normal tissues. Our results show that CCL6 can be either a positive or negative target for Myc oncoproteins. The chemokine may alter tumor behavior by relieving its growth factor dependency and by promoting invasiveness as a result of local tissue apoptosis.
Yi
Fenghua
F
Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Jaffe
Ronald
R
Prochownik
Edward V
EV
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
D019742:Chemokines, CC; D016271:Proto-Oncogene Proteins c-myc; C070959:Ccl6 protein, mouse