Fig. 8: SKP2 effects are mediated by p27Kip1 and p57Kip2 degradation.
a A model showing that in myoblasts and RMS cells that are both proliferating, H3K27ac (Ac) enrichment at SKP2 DNA regulatory regions allows MYOD, which is bound on these regions, to induce the expression of SKP2 thus supporting proliferation (left). Upon differentiation cues, reduction of H3K27ac enrichment results in a closed chromatin conformation, impairing MYOD ability to induce SKP2 transcription. These events promote differentiation, which is inhibited in RMS (right). b A model showing that in RMS cells, MYOD induces the expression of SKP2, which in turn associates with the SCF/CRL1 complex to promote ubiquitylation and proteasomal degradation of p27Kip1 and p57Kip2 by direct interaction and p21Cip1 in an indirect way, promoting oncogenic features (left). These SKP2 functions can be suppressed by SKP2 silencing (upper right) or by its functional inhibition by the SKP2 inhibitor SMIP004 or the NEDDylation inhibitor MLN4924 (lower right) to block RMS oncogenic properties. NAE NEDD8-activating enzyme, Ub Ubiquitin, N8 NEDD8. Created with BioRender.com.
