title: CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement.
abstract: Chimeric oncoproteins created by chromosomal translocations are among the most common genetic mutations associated with tumorigenesis. Malignant mucoepidermoid salivary gland tumors, as well as a growing number of solid epithelial-derived tumors, can arise from a recurrent t (11, 19)(q21;p13.1) translocation that generates an unusual chimeric cAMP response element binding protein (CREB)-regulated transcriptional coactivator 1 (CRTC1)/mastermind-like 2 (MAML2) (C1/M2) oncoprotein comprised of two transcriptional coactivators, the CRTC1 and the NOTCH/RBPJ coactivator MAML2. Accordingly, the C1/M2 oncoprotein induces aberrant expression of CREB and NOTCH target genes. Surprisingly, here we report a gain-of-function activity of the C1/M2 oncoprotein that directs its interactions with myelocytomatosis oncogene (MYC) proteins and the activation of MYC transcription targets, including those involved in cell growth and metabolism, survival, and tumorigenesis. These results were validated in human mucoepidermoid tumor cells that harbor the t (11, 19)(q21;p13.1) translocation and express the C1/M2 oncoprotein. Notably, the C1/M2-MYC interaction is necessary for C1/M2-driven cell transformation, and the C1/M2 transcriptional signature predicts other human malignancies having combined involvement of MYC and CREB. These findings suggest that such gain-of-function properties may also be manifest in other oncoprotein fusions found in human cancer and that agents targeting the C1/M2-MYC interface represent an attractive strategy for the development of effective and safe anticancer therapeutics in tumors harboring the t (11, 19) translocation.
authors: Department of Cancer Biology.
authors: Antonio L
authors: AL
authors: Amelio
authors: IT Informatics.
authors: Mohammad
authors: M
authors: Fallahi
authors: Department of Cancer Biology.
authors: Franz X
authors: FX
authors: Schaub
authors: Departments of Medicine.
authors: Min
authors: M
authors: Zhang
authors: Department of Cancer Biology.
authors: Mariam B
authors: MB
authors: Lawani
authors: Department of Cancer Biology.
authors: Adam S
authors: AS
authors: Alperstein
authors: Translational Research Institute and Department of Molecular Therapeutics, and.
authors: Mark R
authors: MR
authors: Southern
authors: Genomics Core, The Scripps Research Institute, Jupiter, FL 33458; and.
authors: Brandon M
authors: BM
authors: Young
authors: Molecular Genetics and Microbiology, and.
authors: Lizi
authors: L
authors: Wu
authors: Departments of Medicine,Anatomy and Cell Biology, Shands Cancer Center, University of Florida, Gainesville, FL 32610.
authors: Maria
authors: M
authors: Zajac-Kaye
authors: Departments of Medicine.
authors: Frederic J
authors: FJ
authors: Kaye
authors: Department of Cancer Biology.
authors: John L
authors: JL
authors: Cleveland
authors: Department of Cancer Biology,Translational Research Institute and Department of Molecular Therapeutics, and conkright@scripps.edu.
authors: Michael D
authors: MD
authors: Conkright
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D053263:Gene Regulatory Networks; D016259:Genes, myc; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018298:Mucoepidermoid Tumor / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D012468:Salivary Gland Neoplasms / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014178:Translocation, Genetic
chemical_list: C115163:CREB1 protein, human; C500984:CRTC1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C471297:MAML2 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D014157:Transcription Factors