The c-myc apoptotic response is not intrinsic to blocking terminal myeloid differentiation.
It has previously been shown that deregulated c-myc blocks terminal myeloid differentiation and prematurely recruits both the Type I and II CD95/Fas apoptotic pathways, promoting an incompletely penetrant apoptotic response. In this work it is shown that deregulated expression of either mycER or mycERtrade mark variants also blocked terminal myeloid differentiation but failed to induce the apoptotic response, demonstrating that c-myc can block differentiation independent of the apoptotic response. The failure of the mycERtrade mark transgene to cause the apoptotic response is associated with reduced levels of RIP1 expression, increased Mcl-1 expression and activation of both NF-kB and Akt. In addition, deregulating expression of RIP1 in M1mycERtrade mark cells restored the apoptotic response. Thus altering c-Myc or its downstream effectors can influence the balance between apoptosis and survival, and ultimately the oncogenic potential of the c-myc oncogene. This knowledge can be exploited to manipulate the downstream effectors, such as RIP1, to promote apoptosis and drive the death of cancer cells.
D'Angelo
Santo
S
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Liebermann
Dan
D
Hoffman
Barbara
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D022423:Myeloid Cells / Q000166:cytology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism; D019076:Transgenes; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D053418:Death Domain Receptor Signaling Adaptor Proteins; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D013629:Tamoxifen; C016601:afimoxifene; D051057:Proto-Oncogene Proteins c-akt; D053422:Receptor-Interacting Protein Serine-Threonine Kinases