1: J Exp Med. 2005 Nov 14; [Epub ahead of print] 

Coordinated oncogenic transformation and inhibition of host immune responses by
the PAX3-FKHR fusion oncoprotein.

Nabarro S, Himoudi N, Papanastasiou A, Gilmour K, Gibson S, Sebire N, Thrasher
A, Blundell MP, Hubank M, Canderan G, Anderson J.

Unit of Molecular Haematology and Cancer Biology, Institute of Child Health,
London WC1N 1EH, England, UK.

Tumors have evolved elaborate mechanisms for evading immune detection, such as
production of immunoinhibitory cytokines and down-regulation of major
histocompatibility complex (MHC) expression. We have studied PAX3-FKHR as an
example of an oncogenic fusion protein associated with an aggressive metastatic
cancer. We show that PAX3-FKHR alters expression of genes that are normally
regulated by Janus kinase/signal transducer and activator of transcription
(STAT) signaling pathways. This occurs as a result of a specific interaction
between PAX3-FKHR and the STAT3 transcription factor, which results in a
dramatic reduction in tumor MHC expression, and an alteration in local cytokine
concentrations to inhibit surrounding inflammatory cells and immune detection.
Collectively, these data show that an oncogenic transcription factor can promote
tumor growth and tissue invasion while inhibiting local inflammatory and immune
responses. This is the first time that an immunomodulatory role has been
described for an oncogenic fusion protein.

PMID: 16287709 [PubMed - as supplied by publisher]


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2: J Biol Chem. 2002 Apr 26;277(17):15132-41. Epub 2002 Feb 5. 

Pax3 down-regulation and shut-off of melanogenesis in melanoma B16/F10.9 by
interleukin-6 receptor signaling.

Kamaraju AK, Bertolotto C, Chebath J, Revel M.

Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot,
Israel.

The microphthalmia-associated transcription factor (Mitf) is essential for
melanocytic lineage development and for expression of melanogenic enzymes, such
as tyrosinase. Interleukin-6 receptor/interleukin-6 chimera (IL6RIL6) induces in
B16/F10.9 melanoma cells a loss of melanogenesis preceded by a sharp decrease in
Mitf mRNA and gene promoter activity. In the Mitf promoter, the main cis-acting
element mediating the IL6RIL6 effect is shown to be the binding site of Pax3, a
paired homeodomain factor regulating among other things the development of
melanocytes. Pax3 protein and mRNA levels decline steadily after IL6RIL6
treatment, and overexpression of an ectopic Pax3 cDNA suppresses the Mitf
promoter inhibition. Loss of the synergism between Pax3 and Sox10, a high
mobility group domain costimulatory factor, seems to be critical in the rapid
decrease in Mitf gene expression. The Pax3 down-regulation in IL6RIL6-induced
F10.9 cell is linked to growth arrest and transdifferentiation to a glial cell
phenotype. IL6RIL6 stimulates the interleukin-6 family cytokine receptor gp130,
leading to the rapid phosphorylation of Stat3 on tyrosine 705. This
phosphorylation is required for Pax3 down-regulation and Mitf promoter silencing
since these are inhibited in F10.9 cells overexpressing the Stat3 DN-mutant
Y705F.

PMID: 11830592 [PubMed - indexed for MEDLINE]


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