Review
Regulation of the p53-MDM2 pathway by 14-3-3 σ and other proteins

https://doi.org/10.1016/j.semcancer.2006.03.009Get rights and content

Abstract

The 14-3-3 σ (sigma) protein, a unique member of 14-3-3 family, is a negative regulator of the cell cycle and is induced by p53 to initiate cell cycle checkpoint control after DNA damage. Among the 14-3-3 family members, 14-3-3 σ is uniquely induced by p53 and has a positive feedback effect on p53 activity in response to DNA damage. Although 14-3-3 σ is linked to p53-regulated cell cycle checkpoint control, the detailed mechanisms of cell cycle regulation by 14-3-3 σ remain unclear. Decreased expression of 14-3-3 σ was reported in several types of carcinomas, suggesting that the negative regulatory role of 14-3-3 σ in the cell cycle is compromised during tumorigenesis. Given the fact that p53's tumor suppressive function is lost in almost half of all human cancers and that 14-3-3 σ's activity is linked to the p53 network, a perspective regarding the p53/14-3-3 σ relationship is needed for cancer research. Here we discuss the mechanisms by which 14-3-3 σ-stabilizes p53 with the hope that these insights may be applied to develop targeted therapeutic strategies for cancer treatment.

Introduction

The 14-3-3 family of proteins has many diverse functions, including critical roles in signal transduction pathways and cell cycle regulation [1], [2], [3]. In mammalian species the 14-3-3 family is comprised of the seven highly conserved isoforms β, ɛ, η, γ, τ (also called θ), ζ, and σ. Among the family members, 14-3-3 σ is unique. The 14-3-3 σ gene is induced by the p53 tumor suppressor protein in response to DNA damage and differs from other isoforms in structure. 14-3-3 σ has unique amino acids (Met202, Asp204, and His206) that may be responsible for binding to particular ligands that are not recognized by other 14-3-3 members [4], [5].

14-3-3 σ was originally characterized as a human mammary epithelial-specific marker (HME1) [6] that is down-regulated in mammary carcinoma cells. 14-3-3 σ negatively regulates the cell cycle by interacting with cylin-dependent kinases (CDKs) [7]. 14-3-3 σ shares cyclin–Cdk2 binding motifs with different cell cycle regulators, including p107, p130, p21Cip1, p27Kip1, and p57Kip2 and is associated with cyclin–Cdk complexes in vitro and in vivo. Reintroduction of 14-3-3 σ in breast cancer cell lines leads to inhibition of CDK-associated histone H1 kinase activity and inhibition of cell growth. After DNA damage 14-3-3 σ is induced by p53. Immunofluorescence studies indicate that 14-3-3 σ sequesters Cdc2 and Cdk2 complexes from the nucleus to the cytoplasm, which contributes to the G2 arrest in response to DNA damage [7], [8]. Importantly, 14-3-3 σ also positively regulates p53 stability and potentiates p53 transcriptional activity [9], thereby executing a positive feedback effect on p53 activity.

Given 14-3-3 σ's negative role in cell growth and positive role in potentiating p53 activity, it is conceivable that 14-3-3 σ plays an important role in controlling cancer formation. Indeed, overexpression of 14-3-3 σ can antagonize oncogene-mediated cell growth and transformation in breast cancer cell lines [7]. Conversely, experimental down regulation of 14-3-3 σ allows primary human epithelial cells to grow indefinitely [10], suggesting that a decrease in 14-3-3 σ expression may contribute to tumor formation by promoting cellular immortalization. Importantly, 14-3-3 σ is downregulated in several types of cancer, including breast cancer [11], [12], ovarian cancer [13], salivary gland adenoid cystic carcinoma [14], gastric cancer [15], hepatocellular carcinoma [16], prostate cancer [17], [18], [19], basal cell carcinoma [20], and lung cancer [21]. Usually, the downregulation of 14-3-3 σ is the result of epigenetic silencing by CpG methylation rather than genetic alteration [22], [23]. These observations suggest that the tumor suppressor function of 14-3-3 σ is compromised during tumorigenesis. Recent data indicate that 14-3-3 σ is efficient in inhibiting the tumorigenicity of ErbB2-overexpressing cells [9], Akt-activating cells [24], [25] and nasopharyngeal carcinoma cells [26]. These data provide compelling evidence that 14-3-3 σ can function as a tumor suppressor.

The observation that 14-3-3 σ has positive feedback effect on p53 activity after DNA damage is very intriguing. However, the mechanisms of 14-3-3 σ's role in p53 stabilization and signal transduction have not been fully elucidated. 14-3-3 σ may regulate potential target proteins involved in p53 stabilization by sub-compartimental sequestration, modulating enzyme activity, and facilitating protein–protein interaction. Here we review the potential mechanisms that may be involved in 14-3-3 σ's positive impact on p53 stabilization with a hope that these insights can be applied to investigate 14-3-3 σ's function in the DNA damage response and tumor suppression.

Section snippets

14-3-3 σ is induced by p53 in response to DNA damage

Importantly, 14-3-3 σ is the only 14-3-3 isoform induced by tumor suppressor protein p53 in response to gamma irradiation and other DNA-damaging agents [27]. The 14-3-3 σ promoter contains a p53 response element; therefore, p53 can directly transactivate the expression of 14-3-3 σ. 14-3-3 σ induction results in a G2 arrest [27]. p53, dubbed ‘a guardian of the genome’ [28], is a critical regulator of cell proliferation in response to DNA damage. p53 activation causes cell arrest, and subsequent

14-3-3 σ has a positive feedback effect on p53

The 14-3-3 σ gene was identified as a p53-inducible gene involved in cell cycle checkpoint control after DNA damage [27]. The 14-3-3 σ protein was also characterized as a negative regulator of cyclin-dependent kinases (CDKs) [7]. Thus, the negative roles of p53 and 14-3-3 σ in cell cycle progression suggested a possible linkage of p53 and 14-3-3 σ. Members of the 14-3-3 protein family have been shown to act as adapter proteins binding to many signal proteins to exert biological function [34].

Regulation of p53 ubiquitin ligases as a mechanism leading to 14-3-3 σ-mediated p53 stabilization

As indicated above, increased levels of 14-3-3 σ leads to decreasing MDM2 stability thus antagonizing MDM2 activity [9]. Because MDM2 mediates its own ubiquitination and subsequent destabilization in a RING finger-dependent manner, it is possible that 14-3-3 σ affects MDM2 self-ubiquitination. In addition, because 14-3-3 σ has a negative impact on MDM2, it is possible that MDM2-mediated modification on p53 could be diminished. For example, one possible regulation is the neddylation process.

Regulation of MDM2 regulators and 14-3-3 σ-mediated p53 stabilization

To further explore how 14-3-3 σ negatively regulates the activity of MDM2 and thereby stabilizes p53, we will review some of the important mechanisms by which MDM2 activity is regulated (Fig. 3). The data presented thus far clearly indicate that 14-3-3 σ negatively regulates MDM2 and subsequently potentiates the activity of p53. As the loss of 14-3-3 σ occurs in many tumors, the presumably resulting increase in levels of MDM2 may inhibit p53 activity. Numerous other proteins however also

Summary

In this review, we have discussed several modes of MDM2 regulation. The potential involvement of 14-3-3 σ in negatively regulating MDM2 activity could be linked to these regulatory mechanisms. Thus, all the discussed proteins are subject to regulation by 14-3-3 σ. For example, 14-3-3 σ may be able to potentiate the activity of MDM2 negative regulators (Fig. 3, Fig. 4), including ARF, L5, L11, L23, but antagonize the MDM2 positive regulators, including Gankyrin, YY1, KAP1 (Fig. 3, Fig. 4), to

Acknowledgements

We would like to thank the William McGowan Charitable Foundation, the Susan Komen Breast Cancer Foundation, and NIH grant (RO1CA 089266 to M.H. Lee, CA47296 to G. Lozano) for research support. We apologize to our many colleagues whose work that we were unable to cite due to space constraints.

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