The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation.
The mechanism by which activation of the Hedgehog (Hh) pathway modulates differentiation and promotes oncogenesis in specific tissues is poorly understood. We therefore, analysed rhabdomyosarcomas from mice that were haploinsufficient for the Hh-binding protein, Hip1, or for the Hh receptor, Patched 1 (Ptch1). Transfection of the Hh-regulated transcription factor Gli1, which is expressed in a subset of mouse and human rhabdomyosarcomas, suppressed differentiation of myogenic rhabdomyosarcoma lines generated from Hip1+/- and Ptch1+/- mice. The closely related factor, Gli2, had similar effects. Gli1 and Gli2 inhibited myogenesis by repressing the capacity of MyoD to activate transcription. Deletion analysis of Gli1 indicated that multiple domains of Gli1 are required for efficient inhibition of MyoD. Gli1 reduced the ability of MyoD to heterodimerize with E12 and bind DNA, providing one mechanism whereby the Gli proteins modulate the activity of MyoD. This novel activity of Gli proteins provides new insights into how Hh signaling modulates terminal differentiation through inhibition of tissue-specific factors such as MyoD. This mechanism may contribute to the broad role of Hh signaling and the Gli proteins in differentiation decisions and cancer formation.
Gerber
A N
AN
Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA.
Wilson
C W
CW
Li
Y-J
YJ
Chuang
P-T
PT
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D017570:MyoD Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics; D017384:Sequence Deletion; D051820:TCF Transcription Factors / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D058125:Transcription Factor 7-Like 1 Protein; D015533:Transcriptional Activation; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
D004268:DNA-Binding Proteins; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; C489536:Hip1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D017570:MyoD Protein; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2