14-3-3σ positively regulates p53 and suppresses tumor growth

Heng Yin Yang, Yu Ye Wen, Chih Hsin Chen, Guillermina Lozano, Mong Hong Lee

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

The 14-3-3σ (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3σ is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3σ was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3σ in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3σ has not yet been characterized. Here, we studied the link between 14-3-3σ activities and p53 regulation. We found that 14-3-3σ interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3σ expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3σ antagonized the biological ñlnctions functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3σ facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3σ appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3σ inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3σ system. These results defined an important p53 regulatory loop and suggested that 14-3-3σ expression can be considered for therapeutic intervention in cancers.

Original languageEnglish (US)
Pages (from-to)7096-7107
Number of pages12
JournalMolecular and cellular biology
Volume23
Issue number20
DOIs
StatePublished - Oct 1 2003

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Cell Cycle Checkpoints
Cell Cycle
p53 Genes
Growth
Neoplasms
14-3-3 Proteins
Cell Nucleus Active Transport
Ubiquitination
Human Mammary Glands
Tetracycline
Oncogenes
Doxorubicin
DNA Damage
Carcinogenesis
Down-Regulation
Breast Neoplasms
Carcinoma
DNA
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

14-3-3σ positively regulates p53 and suppresses tumor growth. / Yang, Heng Yin; Wen, Yu Ye; Chen, Chih Hsin; Lozano, Guillermina; Lee, Mong Hong.

In: Molecular and cellular biology, Vol. 23, No. 20, 01.10.2003, p. 7096-7107.

Research output: Contribution to journalArticle

Yang, Heng Yin ; Wen, Yu Ye ; Chen, Chih Hsin ; Lozano, Guillermina ; Lee, Mong Hong. / 14-3-3σ positively regulates p53 and suppresses tumor growth. In: Molecular and cellular biology. 2003 ; Vol. 23, No. 20. pp. 7096-7107.
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