p27Kip1 represses the Pitx2-mediated expression of p21Cip1 and regulates DNA replication during cell cycle progression
| Autor: | Maria Jesús Pujol, Oriol Bachs, Arnaud Besson, Atilla Biçer, Edurne Gallastegui, Serena Orlando |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research HEK 293 cells DNA replication Cell cycle Biology medicine.disease_cause Embryonic stem cell Molecular biology Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Transcription (biology) 030220 oncology & carcinogenesis Genetics medicine Gene silencing Carcinogenesis Molecular Biology E2F4 |
| Zdroj: | Oncogene. 36:350-361 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2016.200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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