14-3-3σ Positively Regulates p53 and Suppresses Tumor Growth

Abstract

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

Roles for negative cell regulator 14-3-3σ in control of MDM2 activities

“…As expected, our domain-binding assays indicate that 14-3-3s employs the C-terminal domain to interact with the C-terminal domains of MDM2 or p53 (Figure 2). Hence, on the basis of these results, we have proposed a working model (Figure 7) that incorporates and extends previous findings that 14-3-3s is a positive regulator of p53 (Yang et al, 2003). As presented in the model, when 14-3-3s is not induced in unstressed cells (Figure 7a), 14-3-3s may use its C-terminal domain to interact with C-terminal domains of MDM2 or p53, while MDM2 and p53 are still interacting with each other through respective Nterminal domain.…”

“…Indeed, a strategy to activate p53 in tumor by inhibiting MDM2 activity has been the focus in cancer drug discovery. We previously showed that 14-3-3s inhibits MDM2-mediated p53 ubiquitination (Yang et al, 2003). Thus, 14-3-3s is a potential negative regulator of MDM2.…”

“…We previously showed that 14-3-3s is involved in regulating p53 network by antagonizing the negative impact of MDM2 toward p53 (Yang et al, 2003). However, it remains unclear whether 14-3-3s interacts with MDM2 physically.…”

“…We previously showed that 14-3-3s can block MDM2-mediated p53 degradation (Yang et al, 2003). It has been unclear how 14-3-3s exerts its negative impact.…”

“…14-3-3s is the only 14-3-3 isotype induced by tumor suppressor protein p53 in response to DNA damage (Hermeking et al, 1997). During the DNA damage process, 14-3-3s blocks CDK activity (Chan et al, 1999;Laronga et al, 2000) and also positively regulates p53 stability and potentiates p53 transcriptional activity (Yang et al, 2003). Also, the 14-3-3s is downregulated in breast cancers (Ferguson et al, 2000;Yang et al, 2006).…”