The tumor suppressor p21 regulates cell cycle progression and peaks at mid/late G1. However, the mechanisms regulating its expression during cell cycle are poorly understood. We found that embryonic fibroblasts from p27 null mice at early passages progress slowly through the cell cycle. These cells present an elevated basal expression of p21 suggesting that p27 participates to its repression. Mechanistically, we found that p27 represses the expression of Pitx2 (an activator of p21 expression) by associating with the ASE-regulatory region of this gene together with an E2F4 repressive complex. Furthermore, we found that Pitx2 binds to the p21 promoter and induces its transcription. Finally, silencing Pitx2 or p21 in proliferating cells accelerates DNA replication and cell cycle progression. Collectively, these results demonstrate an unprecedented connection between p27, Pitx2 and p21 relevant for the regulation of cell cycle progression and cancer and for understanding human pathologies associated with p27 germline mutations.
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We would like to thank to Dr Hiroshi Hamada, Dr Chrissa Kioussi, Dr Charles P Emerson and Dr Nobuko Hagiwara for the kind gift of Pitx2-ASE luciferase vector, the expression vector for Pitx2, the expression vector for Zic1 and the expression vector for Sox6, respectively. This work was supported by grants from the Ministerio de Economia y Competitividad (MINECO) SAF2012-38078 and from the Instituto de Salud Carlos III RD12/0036/0054. AB is supported by grants from the Fondation ARC pour la Recherche sur le Cancer, Ligue Nationale Contre le Cancer and Institut National du Cancer. The data set has been deposited in ArrayExpress accession number E-MTAB-2790.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Gallastegui, E., Biçer, A., Orlando, S. et al. p27Kip1 represses the Pitx2-mediated expression of p21Cip1 and regulates DNA replication during cell cycle progression. Oncogene 36, 350–361 (2017). https://doi.org/10.1038/onc.2016.200