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Cell Cycle. 2016; 15(12): 1523–1524.
Published online 2016 April 21. doi:  10.1080/15384101.2016.1171652
PMCID: PMC4934064

A tale of two ends

P53 is one of the most potent tumor suppressors in humans; almost 50% of tumors harbor inactivating or gain of function mutations and the remainder often employ non-genetic means to disarm this critical molecule. A key mechanism of p53 control is through the MDM2 E3 ubiquitin ligase, which functions to inhibit p53 tumor suppressive activity by inhibiting its transcriptional activity and by facilitating its polyubiquitination and subsequent degradation. A number of eloquent studies have highlighted the centrality of MDM2 in p53 regulation, whereby a host of molecules that indirectly affect p53 converge on the MDM2-p53 regulation loop.1

Several recent studies have uncovered novel mechanisms of p53 regulation that are not reliant on MDM2. In our recent study,2 we describe an MDM2-independent mechanism of p53 regulation mediated by the homeodomain-containing transcription factor, Six1. During development, Six1 is widely expressed and plays an important role in proliferation and survival of progenitor cell populations. Six1 expression is low or undetectable in most differentiated tissues, yet numerous studies have demonstrated elevated expression in tumors of multiple origins, where it is linked to metastatic disease.3 Its pro-oncogenic functions include regulation of proliferation, survival, stem/progenitor cell functions, and in carcinomas, epithelial to mesenchymal transitions (EMT),4 therefore closely mimicking its developmental roles.

We uncovered a unique link between Six1 and p53. Overexpression of Six1 in numerous normal and cancerous contexts causes a decrease in p53 protein expression and conversely, knockdown of Six1 increases p53 protein levels. Importantly, MDM2 is dispensable for Six1-mediated downregulation of p53, as neither knockdown of MDM2 with targeted siRNA nor MDM2-targeting small molecules can reverse the ability of Six1 to decrease p53 protein expression.2

Intriguingly, Six1 regulates p53 through a novel mechanism that requires simultaneous inhibition of the ribosomal binding protein, RPL26, and upregulation of the microRNA, miR-27a. Kastan and colleagues previously identified a unique mechanism of regulation of p53 translation, involving the binding of RPL26 to a double stranded RNA that forms between the p53 3′ and 5′ UTRs, which results in increased p53 translation.5 We demonstrate that this mechanism of p53 regulation is even more complex than originally anticipated; the RPL26 binding site in the p53 3′UTR is in close proximity to a microRNA binding site for miR-27a. Thus, for the miR to target and inhibit p53 translation, RPL26 levels must be low. Intriguingly, Six1 simultaneously upregulates miR-27a and downregulates RPL26, thus increasing miR-27a binding and effectively decreasing p53 protein translation.2 These findings have clinical relevance: Because the mechanism of Six1-mediated p53 regulation is independent of MDM2, Six1 overexpression causes marked resistance to MDM2 targeted therapies that are currently in clinical trials. Thus, combination therapies with MDM2-targeted drugs and Six1-targeted drugs (if developed) may be more efficacious in the clinic than either alone (Fig. 1). While our study is one of the first to experimentally demonstrate that an MDM2-independent mechanism of p53 regulation leads to marked resistance to MDM2-targeted therapies, there are a small, but increasing number of other novel p53 regulators recently discovered that mediate their effects independently of MDM2. Notably, several microRNAs and ribosomal proteins are known to bind to the p53 UTRs, all presumably controlling p53 translation.2 The results of our recent study would suggest that these molecules, and potentially many more yet to be discovered, will cause resistance to MDM2 targeted therapies, underscoring the need to identify biomarkers to stratify patients into therapeutically appropriate groups, as well as to develop therapies that may be used in combination with MDM2-p53 interaction inhibitors to re-sensitize the tumors to such drugs.

Figure 1.
Tumors contain heterogeneous populations of cells. Our study indicates that Six1 overexpression is mutually exclusive with MDM2 amplification and that Six1 expression causes resistance to MDM2-targeted therapies. In heterogeneous cell populations, MDM2 ...

Given that a key embryonic transcription factor, Six1, represses p53 levels, it is of interest to speculate as to the developmental function of this regulation. Six1 may regulate p53 to control cellular plasticity, thus maintaining or modulating stem/progenitor cell like activities. Six1 expression results in decreased differentiation and an increase and/or maintenance of stem/progenitor cell populations in multiple tissue types.4 Indeed, overexpression of a pool of 8 genes including Six1, Six2, and the Six1 co-activator, Eya1, reprograms adult cells to embryonic nephron progenitors.6 In contrast, increased p53 has been strongly linked to a differentiated state. Elegant studies with induced pluripotent stem (iPS) cells have shown p53 to be a critical barrier for reprogramming.7 Additionally, loss of p53 results in higher concentrations of stem/progenitor cell populations that are capable of differentiating down multiple lineages to generate complete tissues.7 Together, these studies highlight inverse roles for Six1 and p53 in stem/progenitor populations during development and in the regeneration/repair of adult tissues, suggesting that during development/regeneration a role for Six1 may be to maintain low levels of p53 and increase cellular plasticity in a tissue specific manner. Indeed, this role may be key to the oncogenic function of re-expressed Six1 in human tumors.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.


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[6] Hendry CE, et al. . J Am Soc Nephrol 2013; 24:1424-34; PMID:23766537; [PubMed] [Cross Ref]
[7] Spike BT, Wahl GM. p53, Stem Cells, and Reprogramming: Tumor Suppression beyond Guarding the Genome. Genes Cancer 2011; 2:404-19; PMID:21779509; [PMC free article] [PubMed] [Cross Ref]

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