Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis.
Many early stage human tumors display markers of a DNA-damage response (DDR), including ataxia telangiectasia mutated (ATM) kinase activation. This suggests that DNA damage accumulates during the process of carcinogenesis and that the ATM-dependent response to this damage may function to suppress cancer progression. The E2F3a transcription factor plays an important role in regulating cell proliferation and is amplified in a subset of human cancers. Similar to human premalignant lesions, we find activated ATM and other markers of the DDR in the hyperplastic epidermis of transgenic mice expressing E2F3a through a keratin 5 (K5) promoter. Primary keratinocytes from K5 E2F3a transgenic mice contain increased levels of DNA breaks compared to wild-type cells. E2F3a overexpression also induced DNA damage in primary human fibroblasts that was inhibited by blocking DNA replication. The absence of ATM impaired apoptosis induced by E2F3a and treating K5 E2F3a transgenic mice with caffeine, an inhibitor of ATM and Rad3-related (ATR), promoted skin tumor development. These findings demonstrate that the deregulated expression of E2F3a causes DNA damage under physiological conditions and indicate that the ATM-dependent response to this damage is important for the induction of apoptosis and tumor suppression.
Paulson
Q X
QX
Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA.
Pusapati
R V
RV
Hong
S
S
Weaks
R L
RL
Conti
C J
CJ
Johnson
D G
DG
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D020552:Comet Assay; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050699:E2F3 Transcription Factor; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases