c-Myc overcomes cell cycle inhibition by CBFbeta-SMMHC, a myeloid leukemia oncoprotein.
Thirty percent of acute myeloid leukemia cases express a Core Binding Factor (CBF) oncoprotein or harbor point mutations in one or both AML1 (RUNX1) genes. Each of these alterations reduces endogenous CBF activities. CBFbeta-SMMHC is expressed from the inv(16) chromosome in 8% of AML cases and inhibits endogenous CBF DNA-binding. Inhibition of CBF reduces Retinoblastoma protein phosphorylation and slows the G(1) to S cell cycle transition. c-Myc, a protein which stimulates S phase entry, is over-expressed in one-third of AMLs. We have developed Ba/F3 cell lines in which zinc regulates CBFbeta-SMMHC expression and 4-hydroxytamoxifen activates c-Myc-ER. In these lines, c-Myc-ER overcomes inhibition of cell cycle progression mediated by CBFbeta-SMMHC. CBFbeta-SMMHC does not affect endogenous c-Myc RNA levels, indicating that CBF does not regulate the c-Myc gene. Conversely, c-Myc-ER does not alter CBF DNA-binding activity. Thus, c-Myc-ER acts downstream of CBFbeta-SMMHC to stimulate cell cycle progression. In a subset of CBF leukemias, elevated expression of c-Myc is expected to facilitate the proliferation of the leukemic blasts and thereby potentiate the ability of CBF oncoproteins to block differentiation.
Bernardin
Florence
F
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Baltimore, MD 21231, USA.
Yang
Yandan
Y
Civin
Curt I
CI
Friedman
Alan D
AD
D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016193:G1 Phase / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism*; D051379:Mice; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000819:agonists; D016196:S Phase / Q000235:genetics / Q000502:physiology; D024745:Smooth Muscle Myosins / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism
D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C471254:inv(16) fusion protein, human; D013629:Tamoxifen; C016601:afimoxifene; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains; D015032:Zinc