MXD/MIZ1 complexes activate transcription of MYC-repressed genes

Abstract

MXD proteins are transcription repressors that antagonize the E-box dependent activation of genes by MYC. MYC together with MIZ1 acts also as a repressor of a subset of genes, including cell cycle inhibitor genes such as p15 and p21. A role of MXDs in regulation of MYC-repressed genes is not known. Here we report that MXDs are functionally expressed in U2OS cells and activate transcription of p15 and p21, and other MYC-repressed genes. Activation of transcription was dependent on the interaction of MXDs with MIZ1, and on an intact DNA binding domain. MIZ1-binding deficient MXD mutants interacted with MAX and were active as repressors of MYC-activated genes but failed to activate MYC-repressed genes. Mutant MXDs with reduced DNA binding affinity interacted with MAX and MIZ1 but neither repressed nor activated transcription. Overexpression of MXDs attenuated proliferation of U2OS cells predominantly via MIZ1-dependent induction of p21. Our data show that MXDs and MYC have a reciprocally antagonistic potential to regulate transcription of mutual target genes.

MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products

“…KI-MS2-008 can also synergize with the anti-tumor effects of MAX homodimer stabilizers [423,424]. Furthermore, the transcription repressors, MXD1 and MAD, also inhibit MYC-mediated gene activation [425,426] , by coupling with MAX to hijack E-box regions of target genes and inhibit MYCmediated transcription regulation [425][426][427]. By contrast, JKY-2-169 binds to the MYC-MAX heterodimer and, instead of disrupting heterodimer complex formation, it perturbs MYC/MAX complex binding to canonical DNA E-boxes, antagonizing cancer cell proliferation, cell cycle arrest, and apoptosis in MYC-driven cells [428,429].…”