title: From oncogene to tumor suppressor: the dual role of Myc in leukemia.
abstract: The transcription factor c-Myc strongly stimulates cell proliferation but also regulates apoptosis, senescence, cell competition and cell differentiation, and its elevated activity is a hallmark for human tumorigenesis. c-Myc induces transcription by forming heterodimers with Max and then directly binding DNA at E-box sequences. Conversely, transcription repression depends primarily on the inhibitory interaction of c-Myc/Max with Miz-1 at DNA initiator elements. We recently described a distinct mechanism of c-Myc gene regulation, in which c-Myc interacts with the retinoic acid receptor α (RARα) and is recruited to RAR DNA binding sequences (RAREs). In leukemia cells, this c-Myc/RARα complex functions either as an activator or a repressor of RARα-dependent targets through a phosphorylation switch. Unphosphorylated c-Myc interacts with RARα to repress the expression of RAR targets required for differentiation, thereby aggravating leukemia malignancy. However, if c-Myc is phosphorylated by the kinase Pak2, the c-Myc/RARα complex activates transcription of those same genes to stimulate differentiation, thus reducing tumor burden. Here, we discuss the role of c-Myc in balancing proliferation and differentiation and how modulating this previously unidentified c-Myc activity might provide alternative therapies against leukemia and possibly other types of tumors.
authors.affiliation: Centre de Regulació Genòmica (CRG) and UPF, Barcelona, Spain.
authors.forename: Iris
authors.initials: I
authors.lastname: Uribesalgo
authors.forename: Salvador Aznar
authors.initials: SA
authors.lastname: Benitah
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D055153:Stem Cell Niche; D014212:Tretinoin / Q000494:pharmacology; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D016271:Proto-Oncogene Proteins c-myc; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C082925:retinoic acid receptor beta; D014212:Tretinoin; C515907:PAK2 protein, human; D054462:p21-Activated Kinases