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p53 regulates maternal reproduction through LIF

Abstract

Extensive studies have shown that p53 is important in tumour prevention1. However, little is known about its normal physiological function. Here we show that p53 is important in reproduction, in a gender-specific manner. Significant decreases in embryonic implantation, pregnancy rate and litter size were observed in matings with p53-/- female mice but not with p53-/- male mice. The gene encoding leukaemia inhibitory factor (LIF), a cytokine critical for implantation2, was identified as a p53-regulated gene that functions as the downstream mediator of this effect. p53 can regulate both basal and inducible transcription of LIF. Loss of p53 decreased both the level and function of LIF in uteri. Lower LIF levels were observed in the uteri of p53-/- mice than in those of p53+/+ mice, particularly at day 4 of pregnancy, when transiently induced high levels of LIF were crucial for embryonic implantation. This observation probably accounts for the impaired implantation of embryos in p53-/- female mice. Administration of LIF to pregnant p53-/- mice restored maternal reproduction by improving implantation. These results demonstrate a function for p53 in maternal reproduction through the regulation of LIF. Evidence is accumulating that p53 may have a similar function in humans.

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Figure 1: p53 regulates the expression of LIF genes.
Figure 2: p53 regulates LIF expression in mouse uterus during implantation.

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Acknowledgements

We thank S. Christen for critical review of the manuscript, and I. Snyder and the staff of the University of Medicine and Dentistry of New Jersey animal facility for providing animal care. This research was supported by grants from the Breast Cancer Research Foundation and the National Cancer Institute.

Author Contributions W.H., Z.F. and A.J.L. designed the research. W.H., Z.F. and A.K.T. performed the research. W.H., Z.F. and A.J.L. analysed data and wrote the paper.

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Correspondence to Arnold J. Levine.

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Hu, W., Feng, Z., Teresky, A. et al. p53 regulates maternal reproduction through LIF. Nature 450, 721–724 (2007). https://doi.org/10.1038/nature05993

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