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Flipping the Switch

April 5, 2011

Murine SCCs resemble human SCCAsk a cancer researcher for a one-word description of p53, and the first adjective to tumble out likely would be complex.  Another would be maddening. Since the discovery of TP53 (the gene) and p53 (its protein product) in 1979, this elusive tandem has taken researchers on a wild ride, careening through concepts such as proto-oncogene (false), tumor suppressor gene (correct), cell-cycle checkpoints, transcription, DNA repair, programmed cell death, senescence, chromosomal segregation.  And we're just getting started.

In the late 1990s, scientists thought they finally had p53 cornered.  Make that, double teamed.  Researchers discovered two proteins, called p63 and p73, which shared significant structural homology, or likeness, with p53, suggesting a common evolutionary tie.  What specifically excited researchers, all three proteins had striking homology in their DNA-binding domains.  The hope was p53, p63, and p73 would bind to common DNA promoter sequences and thus regulate the transcription of the same blocks of genes.  If so, scientists stood to benefit in two profound ways.  One, they would learn volumes about how p53 sits "like a spider in his web" at the center of the complex molecular networks that underlie
cancer.[i]  Two, in the roughly half of all cancers in which the p53 spider is directly inactivated to trigger their aberrant growth, researchers would learn how its p63 and p73 cousins step up in its absence to influence the survival of tumor cells and/or their sensitivity to chemotherapy drugs.  Subsequent studies showed both proteins are overexpressed in squamous cell carcinoma, a common type of adult tumor and the most common form of oral cancer.

But what seemed straightforward soon morphed into a biochemical hall of mirrors.  The p63 and p73 genes produce myriad isoforms, or distinct versions, of each protein, some of which completely lacked DNA-binding domains.  This new level of complexity set in motion efforts to go back and obtain a more systematic count of the isoforms and, importantly, account for the gene-transcribing machinery that they regulate in the cell nucleus.  At the top of the list were the microRNAs, a non-coding, small RNA molecule synthesized from intronic regions of DNA (a nucleotide sequence edited out of the final protein by RNA splicing).  At last count, the human genome contains more than 940 microDNAs.  They bind post translationally to complementary sequences of messenger RNA to inhibit or accelerate their degradation and thereby regulate gene and protein expression, including in tumor cells.

In the February 1 issue of The Journal of Clinical Investigation, a team of NIDCR grantees offers a remarkable glimpse into the powerful biochemical information to be gleaned from p63, p73, and its microRNAs.  The scientists discovered a microRNA called miR-193a that p63 and p73 directly regulate and which serves as an on-off switch to promote either cell death or survival. According to the researchers, this discovery is particularly interesting because the go-to platinum-based chemotherapy drug cisplatin appears to inadvertently eliminate p63 from the mix, flicking the microRNA switch into the pro-survival "on" position, and helping squamous cell carcinoma tumor cells to withstand the drug's deadly effects.

Indeed, in a proof-of-principle test of their initial data, the scientists measured the expression levels of miR-193a in 23 head and neck squamous cell carcinomas - all of which were treated preoperatively with the same cisplatin-containing chemotherapy regimen.  They found the two most treatment-resistant tumors ranked in the top three for highest expression levels of miR-193a.

Although their data are preliminary, the scientists say the results suggest that further research is needed to determine whether disrupting the miR-193a switch will assist cisplatin and other chemotherapy drugs to kill squamous cell carcinoma cells in p53-negative tumors.


  • Ory B, Ramsey MR, Wilson C, Vadysirisack DD, Forster N, Rocco JW, Rothenberg SM, Ellisen LW, “A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma,” J Clin Invest, 2011 Feb 1:121(2):809-820.

Also see the following perspective piece:

  • Ory B, Ellisen LW, “A microRNA-dependent circuit controlling p63/p73 homeostasis:  p53 family cross-talk meets therapeutic opportunity,” Oncotarget, 2011 March 23

    [i] Hainaut P, Wiman K, "30 years and a long way into P53 research," The Lancet Oncology, 2009: 10: 913-919. 


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This page last updated: February 26, 2014