Oncogenic HoxB7 requires TALE cofactors and is inactivated by a dominant-negative Pbx1 mutant in a cell-specific manner.
The homeobox containing gene HoxB7 is functionally associated with melanoma growth promotion through the direct transactivation of bFGF. Accordingly, the introduction of HoxB7 in the breast cancer line SkBr3 (SkBr3/B7), strongly increases its tumorigenic properties. Here we show that in SkBr3/B7 cells, HoxB7 regulates the expression of TALE Hox cofactors by increasing Pbx2 and Prep1 and decreasing Pbx1. The functional requirement of Hox cofactors in the oncogenic activity of HoxB7 was proven with a dominant-negative Pbx1 mutant, Pbx1NT, which sequesters Prep1 in the cytoplasm. The less aggressive phenotype of the SkBr3/B7/PbxNT cells, evaluated in vitro as well as in vivo, correlated well with increased apoptosis, decreased cycling and up-regulation of p16 and p53. Tumor cell-type specific functional effects of Pbx1NT were observed, possibly related to the presence of different Hox genes in melanoma or breast adenocarcinoma DNA-protein ternary complexes.
Fernandez
Luis C
LC
IFOM, FIRC Institute of Molecular Oncology, via Adamello 16, 20126 Milan, Italy.
Errico
M C
MC
Bottero
L
L
Penkov
D
D
Resnati
M
M
Blasi
F
F
Caré
A
A
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018398:Homeodomain Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D015513:Oncogene Proteins; C090465:PBX2 protein, human; C106682:PKNOX1 protein, human; C435984:PKNOX2 protein, human; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C083400:PBX1 protein, human