Disruption of the Cockayne syndrome B gene impairs spontaneous tumorigenesis in cancer-predisposed Ink4a/ARF knockout mice.
Cells isolated from individuals with Cockayne syndrome (CS) have a defect in transcription-coupled DNA repair, which rapidly corrects certain DNA lesions located on the transcribed strand of active genes. Despite this DNA repair defect, individuals with CS group A (CSA) or group B (CSB) do not exhibit an increased spontaneous or UV-induced cancer rate. In order to investigate the effect of CSB deficiency on spontaneous carcinogenesis, we crossed CSB(-/-) mice with cancer-prone mice lacking the p16(Ink4a)/p19(ARF) tumor suppressor locus. CSB(-/-) mice are sensitive to UV-induced skin cancer but show no increased rate of spontaneous cancer. CSB(-/-) Ink4a/ARF(-/-) mice developed 60% fewer tumors than Ink4a/ARF(-/-) animals and demonstrated a longer tumor-free latency time (260 versus 150 days). Moreover, CSB(-/-) Ink4a/ARF(-/-) mouse embryo fibroblasts (MEFs) exhibited a lower colony formation rate after low-density seeding, a lower rate of H-Ras-induced transformation, slower proliferation, and a lower mRNA synthesis rate than Ink4a/ARF(-/-) MEFs. CSB(-/-) Ink4a/ARF(-/-) MEFs were also more sensitive to UV-induced p53 induction and UV-induced apoptosis than were Ink4a/ARF(-/-) MEFs. In order to investigate whether the apparent antineoplastic effect of CSB gene disruption was caused by sensitization to genotoxin-induced (p53-mediated) apoptosis or by p53-independent sequelae, we also generated p53(-/-) and CSB(-/-) p53(-/-) MEFs. The CSB(-/-) p53(-/-) MEFs demonstrated lower colony formation efficiency, a lower proliferation rate, a lower mRNA synthesis rate, and a higher rate of UV-induced cell death than p53(-/-) MEFs. Collectively, these results indicate that the antineoplastic effect of CSB gene disruption is at least partially p53 independent; it may result from impaired transcription or from apoptosis secondary to environmental or endogenous DNA damage.
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Y
Y
Lu
H
H
Lian
P
P
Sharma
N
N
Schreiber-Agus
R G
RG
Russell
L
L
Chin
G T
GT
van der Horst
D B
DB
Bregman
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D003057:Cockayne Syndrome / Q000235:genetics*; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics* / Q000502:physiology*; D004260:DNA Repair; D045643:DNA Repair Enzymes; D005347:Fibroblasts / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism; D005434:Flow Cytometry; D016158:Genes, p53 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008223:Lymphoma / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014170:Transformation, Genetic; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D018631:ras Proteins / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D000075223:Poly-ADP-Ribose Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D004265:DNA Helicases; C513075:Ercc6 protein, mouse; D018631:ras Proteins; D045643:DNA Repair Enzymes