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Updated: May 23, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Docetaxel and 5-fluorouracil induce human p53 tumor suppressor gene transcription via a short sequence at core
Jui-Chuan Chuang1, Gwo-Tarng Sheu, Pi-Chieh Wang
1Department of Pharmacy, Pojen General Hospital No. 66, Kwang Fu N. Road, Taipei City 105, Taiwan. giuanchuan@pojengh.com.tw
Abstract:
The p53 tumor suppressor protein is involved in cellular defense against agents that can cause genetic damage. Induction of p53 gene expression at transcriptional and post-transcriptional levels by such agents results in p53-regulated gene activation or suppression. Docetaxel (DOC), a member of the taxanes family that is widely used in cancer chemotherapy, activates p53 at the transcriptional level. We demonstrated that p53 is induced by low dose DOC treatment, resulting in MDR-1 gene suppression in human lung cancer cells. To identify the cis-element of p53 promoter that responds to DOC, p53 promoter region was cloned and promoter activity was analyzed on luciferase gene reporter assay. Promoter region (-78 to +129) contained the highest basal p53 promoter activity and deletion of +86 to +129 severely reduced basal promoter activity. Basal promoter region included the 21-bp element (PE21) that determines UV-inducible expression of p53 and mediates DOC-inducible p53 expression. On site-specific mutagenesis of PE21 (-78 to -58), with mutation of ATTG (-62 to -59) to CGGT, completely diminished the response to DOC. The same mutations also inhibited 5-fluorouracil (5-FU)-inducible p53 expression. Our data revealed that a sequence located at PE21 of p53 core promoter regulates p53 induction by chemotherapeutic agents.
Insights
Docetaxel (DOC) chemotherapy induces the p53 tumor suppressor protein in lung cancer cells. A specific promoter element, PE21, is crucial for this DOC-induced p53 expression and MDR-1 gene suppression.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- The p53 protein is a key tumor suppressor involved in cellular defense against DNA-damaging agents.
- Chemotherapeutic agents like Docetaxel (DOC) can induce p53 expression, influencing cancer cell responses.
- Understanding the regulatory mechanisms of p53 induction is vital for optimizing cancer therapy.
Purpose of the Study:
- To identify the specific cis-element in the p53 promoter responsible for Docetaxel (DOC)-induced p53 expression.
- To investigate the role of this element in mediating the suppression of the MDR-1 gene by DOC.
- To explore if this element also regulates p53 induction by other chemotherapeutic agents.
Main Methods:
- Cloning of the p53 promoter region and analysis of promoter activity using a luciferase gene reporter assay.
- Site-specific mutagenesis of the identified promoter element (PE21) to assess its functional role.
- Evaluation of p53 induction and MDR-1 gene suppression in human lung cancer cells treated with DOC and 5-fluorouracil (5-FU).
Main Results:
- The p53 promoter region from -78 to +129 exhibited the highest basal activity, with deletion of +86 to +129 significantly reducing it.
- A 21-bp element (PE21) within this region was identified as essential for both basal and DOC-inducible p53 expression.
- Mutagenesis of the ATTG sequence within PE21 abolished DOC-induced p53 expression and also inhibited 5-FU-inducible p53 expression.
Conclusions:
- A specific sequence within the PE21 element of the p53 core promoter is critical for regulating p53 induction by chemotherapeutic agents like Docetaxel.
- This finding provides insight into the molecular mechanisms underlying p53 activation by chemotherapy.
- The PE21 element represents a potential target for modulating p53 responses in cancer treatment.
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