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A novel evolutionarily conserved element is a general transcriptional repressor of p21WAF¹/CIP¹

Weiguo Xu1, Qi Zhu, Zhenghua Wu

  • 1School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.

Cancer Research
|October 16, 2012
PubMed

Insights

Oxaliplatin effectively induces p21 expression in p53-negative cancer cells by derepressing a conserved Sp1/Sp3 element in the p21 promoter. This finding offers a new strategy for cancer management by targeting this regulatory repressor.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genomics

Background:

  • Inducing p21 (WAF1/CIP1/Cdkn1a) expression is crucial for managing p53-negative cancers.
  • The precise mechanisms regulating p21 expression in these cells remain incompletely understood.

Purpose of the Study:

  • To investigate how common chemotherapeutic drugs, specifically oxaliplatin, induce p21 expression in p53-negative cancer cells.
  • To identify and characterize the regulatory elements and molecular mechanisms involved in oxaliplatin-mediated p21 induction.

Main Methods:

  • Utilized electrophoretic mobility shift and antibody super-shift assays to confirm Sp1/Sp3 binding to the p21 promoter.
  • Analyzed the ENCODE database to identify conserved regulatory elements within the p21 promoter.
  • Performed in vivo competition assays to assess the function of the identified Sp1/Sp3 palindrome element.

Main Results:

  • Oxaliplatin induces p21 expression by derepressing a novel negative regulatory element containing an Sp1/Sp3 palindrome in the p21 proximal promoter (-216 to -236).
  • Oxaliplatin treatment increases Sp1/Sp3 phosphorylation and binding affinity to this element, leading to p21 transcriptional derepression.
  • The Sp1/Sp3 palindrome is the only vertebrate-conserved element in the proximal p21 promoter, highlighting its functional significance.

Conclusions:

  • A conserved Sp1/Sp3 palindrome element in the p21 promoter acts as a repressor of basal p21 expression.
  • Oxaliplatin overcomes this repression through enhanced Sp1/Sp3 activity, providing a novel therapeutic target for p53-negative cancers.

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