The Rb/E2F pathway and Ras activation regulate RecQ helicase gene expression.
Disruption of the Rb (retinoblastoma protein)/E2F cell-cycle pathway and Ras activation are two of the most frequent events in cancer, and both of these mutations place oncogenic stress on cells to increase DNA replication. In the present study, we demonstrate that these mutations have an additive effect on induction of members of the RecQ DNA helicase family. RecQ activity is important for genomic stability, initiation of DNA replication and telomere maintenance, and mutation of the BLM (Bloom's syndrome gene), WRN (Werner's syndrome gene) or RECQL4 (Rothmund-Thomson syndrome gene) family members leads to premature aging syndromes characterized by genetic instability and telomere loss. RecQ family members are frequently overexpressed in cancers, and overexpression of BLM has been shown to cause telomere elongation. Concomitant with induction of RecQ genes in response to Rb family mutation and Ras activation, we show an increase in the number of telomeric repeats. We suggest that this induction of RecQ genes in response to common oncogenic mutations may explain the up-regulation of the genes seen in cancers, and it may provide a means for transformed cells to respond to an increased demand for DNA replication.
Liu
Yongqing
Y
Molecular Targets Program, James Graham Brown Cancer Center, Louisville, KY 40202, USA.
El-Naggar
Shahenda
S
Clem
Brian
B
Chesney
Jason
J
Dean
Douglas C
DC
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D016615:Telomere / Q000378:metabolism; D000071657:Werner Syndrome Helicase; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050684:E2F Transcription Factors; D007527:Isoenzymes; D016160:Retinoblastoma Protein; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse; D018631:ras Proteins