Transcription activity is required for p53-dependent tumor suppression.
As a transcription factor, the critical tumor suppressor, p53, directly regulates the transcription of hundreds of genes, leading to cell-cycle arrest, apoptosis, cellular senescence and differentiation. Although it has been assumed that p53 transcription activity is critical for tumor suppression, this assumption has been increasingly contested by recent findings of transcription-independent roles of p53 in apoptosis as well as findings that none of the mutant mice lacking important p53 transcription targets are cancer prone. On the basis of previous findings that p53 transcription activity is abolished in p53(QS) (Leu25Trp26 to Gln25Ser26) knock-in mouse cells after DNA damage, to determine the importance of transcription activity of p53 in tumor suppression, we generated knock-in mice that can conditionally express p53(QS) protein in a Cre-dependent manner. By breeding the knock-in mice with Lck-Cre transgenic mice that specifically express Cre in thymocytes, we show that p53-dependent suppression of thymic lymphomas is abolished in thymocytes expressing high levels of p53(QS) protein. In addition, p53(QS) protein is accumulated in some of the thymic tumors. Therefore, p53 transcription activity induced by DNA damage is required for tumor suppression. Together with the findings that the disruption of various p53-dependent functions individually fails to promote cancer, our findings indicate that various transcription-dependent functions of p53 must collaborate to efficiently suppress tumorigenesis.
Gaidarenko
O
O
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
Xu
Y
Y
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009362:Neoplasm Metastasis; D013945:Thymoma / Q000235:genetics / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53