The Niche

p53 at ISSCR: not just for cancer anymore

Most scientists who think about p53 are probably working on cancer rather than pluripotency, but a suite of talks is putting that protein on stem cell biologists’ radar.

At ISSCR, Shinya Yamanaka of Kyoto University presented data showing that both p21 and p53 offer barriers to reprogramming: attempts to reprogram fibroblasts that lack p53 are much, much more efficient. Konrad Hochedlinger at Harvard described similar results. Hochedlinger and others have created iPS cells with inducible versions of pluripotency genes, then used them to generate mice whose cells already contain the genesnecessary for reprogramming; no new viral transfection needed. Shockingly, though, activating these genes in fibroblasts made from these ‘reprogramming-ready’ mice does not yield very efficient reprogramming rates. However, Hochedlinger’s lab found that if p53 is knocked out in these secondary cells, the reprogramming rates soar to over 80%. Hochedlinger has been experimenting with genes associated with senescence (INK4a/ARF) as well as blood cell types at varying stages from senescence. He found that, generally, the further a cell is from the senescent state, (i.e. the more divisions it has left in it) the more efficiently it reprograms.

Jacob Hanna from Rudolf Jaenisch’s lab at the Whitehead presented results adding another insight to these finding. He and his colleagues worked with several passages of blood cells that already contained insertions of pluripotency genes. They found that, given enough time, just about any cell can be converted to pluripotency. Suppressing p53 clearly has the power to boost reprogramming rates, possibly because the knockdown of p53 causes cells to divide twice as fast for reasons likely to be linked to the cell cycle. (But of course, other explanations will be found elsewhere. Hanna, for example, also found that overexpressing Nanog accelerates reprogramming independently of accelerating cell cycle.)

The first publication I’m aware of that linked p53 to the efficiency of induced pluripotency was by Hongkui Deng in Cell Stem Cell in November last year. It’s certainly not going to be the last.


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