Abstract
In some cell types either DNA damage or p53 expression leads to minimal cell death, while combining the two leads to a strong apoptotic response. To further understand features of p53 that contribute to this increased cell death we used clones of H1299 cells that express wild-type or several mutant forms of p53 under a tetracycline-regulated promoter. In these cells the induction of wild-type p53 leads to significant apoptosis only when combined with exposure to a number of chemotherapeutic agents. A common target of p53, p21, is itself not sufficient to cause apoptosis in the presence of these chemotherapeutic compounds. Many agents also effectively increase cell death when a transcriptionally-defective p53, p53[gln22ser23], is induced, although a dramatic exception is treatment with 5-FU, which strongly cooperates with wild-type but not p53[gln22ser23]. Our results with 5-FU thus show that genetically separable functions of p53 are involved in its ability to respond to DNA-damaging agents to induce apoptosis. Notably as well, deleting the C-terminal 30 amino acids of p53 does not affect this cooperative effect with DNA-damaging agents. By contrast, a p53 mutant lacking the PXXP-domain between residues 60-90, while at least partially transcriptionally-competent, cannot be rendered apoptotic by any compounds that we tested. Thus the PXXP domain provides an essential component of the ability of p53 to respond to DNA-damaging agents to cause cell death.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 9-21 |
| Number of pages | 13 |
| Journal | Oncogene |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 3 2002 |
| Externally published | Yes |
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Keywords
- Anti-neoplastics
- Apoptosis
- p53
- Proline-rich domain
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells. / Baptiste, Nicole; Friedlander, Philip; Chen, Xinbin; Prives, Carol.
In: Oncogene, Vol. 21, No. 1, 03.01.2002, p. 9-21.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells
AU - Baptiste, Nicole
AU - Friedlander, Philip
AU - Chen, Xinbin
AU - Prives, Carol
PY - 2002/1/3
Y1 - 2002/1/3
N2 - In some cell types either DNA damage or p53 expression leads to minimal cell death, while combining the two leads to a strong apoptotic response. To further understand features of p53 that contribute to this increased cell death we used clones of H1299 cells that express wild-type or several mutant forms of p53 under a tetracycline-regulated promoter. In these cells the induction of wild-type p53 leads to significant apoptosis only when combined with exposure to a number of chemotherapeutic agents. A common target of p53, p21, is itself not sufficient to cause apoptosis in the presence of these chemotherapeutic compounds. Many agents also effectively increase cell death when a transcriptionally-defective p53, p53[gln22ser23], is induced, although a dramatic exception is treatment with 5-FU, which strongly cooperates with wild-type but not p53[gln22ser23]. Our results with 5-FU thus show that genetically separable functions of p53 are involved in its ability to respond to DNA-damaging agents to induce apoptosis. Notably as well, deleting the C-terminal 30 amino acids of p53 does not affect this cooperative effect with DNA-damaging agents. By contrast, a p53 mutant lacking the PXXP-domain between residues 60-90, while at least partially transcriptionally-competent, cannot be rendered apoptotic by any compounds that we tested. Thus the PXXP domain provides an essential component of the ability of p53 to respond to DNA-damaging agents to cause cell death.
AB - In some cell types either DNA damage or p53 expression leads to minimal cell death, while combining the two leads to a strong apoptotic response. To further understand features of p53 that contribute to this increased cell death we used clones of H1299 cells that express wild-type or several mutant forms of p53 under a tetracycline-regulated promoter. In these cells the induction of wild-type p53 leads to significant apoptosis only when combined with exposure to a number of chemotherapeutic agents. A common target of p53, p21, is itself not sufficient to cause apoptosis in the presence of these chemotherapeutic compounds. Many agents also effectively increase cell death when a transcriptionally-defective p53, p53[gln22ser23], is induced, although a dramatic exception is treatment with 5-FU, which strongly cooperates with wild-type but not p53[gln22ser23]. Our results with 5-FU thus show that genetically separable functions of p53 are involved in its ability to respond to DNA-damaging agents to induce apoptosis. Notably as well, deleting the C-terminal 30 amino acids of p53 does not affect this cooperative effect with DNA-damaging agents. By contrast, a p53 mutant lacking the PXXP-domain between residues 60-90, while at least partially transcriptionally-competent, cannot be rendered apoptotic by any compounds that we tested. Thus the PXXP domain provides an essential component of the ability of p53 to respond to DNA-damaging agents to cause cell death.
KW - Anti-neoplastics
KW - Apoptosis
KW - p53
KW - Proline-rich domain
UR - http://www.scopus.com/inward/record.url?scp=0037012041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037012041&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1205015
DO - 10.1038/sj.onc.1205015
M3 - Article
C2 - 11791172
AN - SCOPUS:0037012041
VL - 21
SP - 9
EP - 21
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 1
ER -