Science for Health
11 December 2012
Differentiated cells can be converted into induced pluripotent stem cells (iPSCs) through the combined action of specific transcription factors, including SOX2. The mechanisms responsible for the transcriptional silencing of these pluripotency genes in differentiated cells are poorly understood but are expected to provide clues about the molecular mechanisms governing stem cell biology and cancer.
Recently, it has been shown that some tumor suppressors oppose reprogramming and limit the efficiency of the process. In this study, the potential role of p27 was examined in this context. p27Kip1 is a negative cell cycle regulator that binds and inhibits cyclin dependent kinases and low protein levels of p27 constitute a poor prognosis marker for several types of cancer. Moreover, p27 germline mutations are responsible for a subset of human multiple endocrine neoplasia (MEN) syndromes, notably characterized by pituitary tumors. This phenotype is recapitulated in p27 null mice that are also affected by gigantism and organ hyperplasia.
Manuel Serrano, in collaboration with Robin Lovell-Badge (pictured) in the Division of Stem Cell Biology and Developmental Genetics, has investigated the role of tumor suppressors during reprogramming, and observed that cells lacking p27 can be reprogrammed into induced pluripotent stem cells (iPSCs) in the absence of ectopic SOX2. They also observed that p27 null iPSCs fail to fully repress SOX2 upon differentiation. Moreover, several tissues in P27 null mice, including brain, lung, and retina show elevated basal expression of SOX2, suggesting that p27 contributes to the repression of SOX2. In agreement with this hypothesis, the authors show that p27 directly interacts with a Sox2 enhancer to induce its transcriptional repression. The physiological relevance of this interaction is highlighted by the rescue of some of the phenotypic defects of p27 null mice, in particular pituitary tumors and retina deficiencies, by Sox2 heterozygosity.
The results reported here demonstrate that the tumor suppressor p27 contributes to the transcriptional repression of Sox2. Collectively, the results demonstrate an unprecedented connection between p27 and Sox2 relevant for reprogramming and cancer and for understanding human pathologies associated with p27 germline mutations. They also provide a link between cell cycle regulation and SOX2, a transcription factor known to be essential for conferring stem cell properties, which might help to explain why SOX2 has such a critical role.
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p27-null pituitary phenotypes are rescued by Sox2-haploinsufficiency
Darker staining = SOX2-positive stem/progenitor cell layer
|Pituitary tumours (%) :||100||30|
Han Li, Manuel Collado, Aranzazu Villasante, Ander Matheu, Cian J. Lynch, Marta Cañamero, Karine Rizzoti, Carmen Carneiro, Gloria Martínez, Anxo Vidal, Robin Lovell-Badge, and Manuel Serrano (2012)
p27Kip1 directly represses Sox2 during embryonic stem cell differentiation
Cell Stem Cell, 11(6):845-852. Publisher abstract.
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