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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2003-06, Vol.63 (11), p.2923-2932
Main Authors: FENGHUA YI, JAFFE, Ronald, PROCHOWNIK, Edward V
Format: Article
Language:English
Subjects:
Animals
Apoptosis - genetics
Apoptosis - physiology
Biological and medical sciences
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - metabolism
Carcinoma, Squamous Cell - pathology
Cell Division - drug effects
Cell Division - physiology
Cell physiology
Cell Survival - genetics
Cell Survival - physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Chemokines, CC - biosynthesis
Chemokines, CC - genetics
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Neoplastic
HeLa Cells
Humans
Mice
Molecular and cellular biology
Neoplasm Metastasis
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - physiology
Transcription, Genetic
Transfection
Up-Regulation
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Summary: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.
ISSN:0008-5472
1538-7445