c-Myc alters the DNA damage-induced G2/M arrest in human mammary epithelial cells.
Effects of c-Myc overexpression on the DNA damage-induced G2/M checkpoint were studied in finite lifespan, normal human mammary epithelial cells (HMECs). Previously, we showed that c-Myc attenuates G1/S arrest and leads to an inappropriate entry of cells with damaged DNA into the S phase, following treatment with ionising radiation (IR). Here we show that, in striking contrast to control cells, c-Myc-overexpressing HMECs demonstrate a significant attenuation of the G2/M arrest, following IR, and enter into inappropriate mitoses. At the molecular level, ectopic overexpression of c-Myc leads to an unusually high level of expression of cyclin B1, and the elevated levels of cyclin B1 were maintained, after gamma-irradiation. Introduction of DNA damage in c-Myc-overexpressing, normal mammary epithelial cells eventually induces apoptosis, indicating a dramatic sensitisation by c-Myc of DNA damage-induced apoptosis. These two remarkable phenotypes, checkpoint attenuation and sensitisation to apoptosis, resulting from a deregulation of the protooncogene c-myc, may produce a unique pattern of alternating cycles, consisting first of amplification of DNA damage, followed by apoptosis-assisted selective pressure. The result of this alternating pattern of damage apoptosis could facilitate the selection of certain genomic alterations required for cellular survival and cellular transformation.
Sheen
J-H
JH
Department of Oncology, Lombardi Comprehensive Cancer Center, Room W417B, Georgetown University Medical Center, 3970 Reservoir Road, Washington, DC 20007-2197, USA.
Woo
J-K
JK
Dickson
R B
RB
D017209:Apoptosis; D015153:Blotting, Western; D001940:Breast / Q000166:cytology* / Q000473:pathology*; D002454:Cell Differentiation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D016195:G2 Phase; D018816:Genes, cdc; D006801:Humans; D007150:Immunohistochemistry; D008938:Mitosis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000494:pharmacology*
D016271:Proto-Oncogene Proteins c-myc