A dominant negative form of p63 inhibits apoptosis in a p53-independent manner
Section snippets
Materials and methods
Cell lines and cell culture. 5637 (bladder cancer) and A549 (lung cancer) cells were grown in RPMI-1640 supplemented with 10% v/v fetal bovine serum, penicillin, and streptomycin. Human foreskin keratinocytes (HFK) were isolated and cultured as described previously [11]. Human telomerase reverse transcriptase (hTERT)-introduced human mammary epithelial (HME) cells were kindly provided by Dr. William Hahn (Dana Farber Cancer Center, Boston).
Antibodies, plasmids, and chemical reagents. Antibodies
ΔNp63α is downregulated following various cellular damages that induce apoptosis
In order to test our hypothesis that ΔNp63α may antagonize p53 in tumorigenesis as observed previously during embryogenesis [2], we checked the p63 status of 15 cancer cell lines of epithelial origin by using Western blot analysis and RT-PCR. This screening revealed that A549—a non-small cell lung carcinoma line—was positive for ΔNp63α expression while the 5637 bladder carcinoma cell line was a ΔNp63α-overexpressing cell line. As compared to human foreskin keratinocytes HFK, the level of ΔNp63α
Discussion
Here, we have presented several lines of evidence suggesting that ΔNp63α plays an antiapoptotic role in the cellular response to DNA damage. Our results demonstrate that the overexpression of ΔNp63α, which has been observed in a number of epithelial cancer cell lines, makes the cells resistant to apoptotic signals on DNA damage. Defective apoptotic responses make the cells highly susceptible to acquiring new mutations that can then lead to malignancy.
The most well-known function of ΔNp63α is
Acknowledgments
We are grateful to Dr. David Kimelman (University of Washington, Seattle) for critically reading the manuscript. We also thank Dr. William Hahn (Dana Farber Institute, Boston) for kindly providing us with human mammary epithelial cells. This work was supported by a fund from the Korea Research Foundation (R01-2003-000-10396-0) and National Cancer Center (3344-20050066).
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New advances in the pathophysiologic and radiologic basis of the exstrophy spectrum
2014, Journal of Pediatric UrologyCitation Excerpt :It also plays a major role in initiating epithelial stratification during development. p63 expresses two different N-terminal isoforms, TAp63 (containing a transactivation domain similar to the TA domain of p53) and an N-terminal truncated isoform of p63 (ΔNp63), due to the presence of an alternative promoter located in intron 3 [10]. TAp63 activates several targets of p53, which promote cell arrest and induce apoptosis.
DNA damage down-regulates ΔNp63α and induces apoptosis independent of wild type p53
2012, Biochemical and Biophysical Research CommunicationsCitation Excerpt :These data suggest that in these cells DNA damage-induced apoptosis is mainly due to the down-regulated expression of ΔNp63α. This is well consistent with the previous reports that ΔNp63α has anti-apoptotic activity [18,26,34]. In addition, ΔNp63α has been documented as an essential survival factor in head and neck squamous cell carcinoma through its ability to suppress p73-dependent apoptosis [35].
Cell density-dependent acetylation of Δnp63α is associated with p53-dependent cell cycle arrest
2012, FEBS LettersCitation Excerpt :These findings suggest that ΔNp63α might contribute to tumorigenesis at an early stage. Furthermore, depletion of ΔNp63α sensitized cancer cells to genotoxic drugs [19,20], suggesting that regulation of ΔNp63α expression may likely be a matter of life and death for normal as well as cancer cells. The epidermal stem cell-specific expression of ΔNp63α is first induced at the transcription level, and the stem cell-specific transcriptional elements are being partially characterized [21,22].
Dominant negative (ΔN) p63α induces drug resistance in hepatocellular carcinoma by interference with apoptosis signaling pathways
2010, Biochemical and Biophysical Research CommunicationsCitation Excerpt :These in vivo findings demonstrate that TAp63 isoforms function as tumor suppressors by regulating senescence through p53-independent pathways [8]. Whereas TAp63 isoforms can induce apoptosis and inhibit cell cycle progression, ΔNp63 isoforms have been shown to enhance proliferation and inhibit apoptosis [9–12]. Furthermore, complete loss of p63 has been shown to be associated with cancer metastasis and poor prognosis [13].
Transcriptional activity of the ΔNp63 promoter is regulated by STAT3
2008, Journal of Biological ChemistryΔNp63 expression is associated with poor survival in ovarian cancer
2008, Annals of OncologyCitation Excerpt :This would imply that ΔNp63 can play an important role in tumor progression. The finding that in our subset of patients, ΔNp63 overexpression and p53 mutations are not related to each other [31], indicates that in this context, ΔNp63 oncogenic role is independent of its transdominant activity on the p53 pathways and could be related to its own transcriptional activity properties. Although this was beyond the scope of this work, we tried to determine whether there was any association between ΔN/TA p63 levels and response to chemotherapy.