p27Kip1 Directly Represses Sox2 during Embryonic Stem Cell Differentiation

Abstract

SummaryThe mechanisms responsible for the transcriptional silencing of pluripotency genes in differentiated cells are poorly understood. We have observed that cells lacking the tumor suppressor p27 can be reprogrammed into induced pluripotent stem cells (iPSCs) in the absence of ectopic Sox2. Interestingly, cells and tissues from p27 null mice, including brain, lung, and retina, present an elevated basal expression of Sox2, suggesting that p27 contributes to the repression of Sox2. Furthermore, p27 null iPSCs fail to fully repress Sox2 upon differentiation. Mechanistically, we have found that upon differentiation p27 associates to the SRR2 enhancer of the Sox2 gene together with a p130-E2F4-SIN3A repressive complex. Finally, Sox2 haploinsufficiency genetically rescues some of the phenotypes characteristic of p27 null mice, including gigantism, pituitary hyperplasia, pituitary tumors, and retinal defects. Collectively, these results demonstrate an unprecedented connection between p27 and Sox2 relevant for reprogramming and cancer and for understanding human pathologies associated with p27 germline mutations.

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

“…Recent studies have shown that p27 plays other essential roles in the regulation of cell differentiation and apoptosis (Liu et al, 2010;Li et al, 2012b).…”

Cdks, cyclins and CKIs: roles beyond cell cycle regulation

“…The effects of Cdk phosphorylation on MyoD can similarly be counteracted by association with p57, which in turn promotes the accumulation of MyoD and the transactivation of muscle-specific genes (Reynaud et al, 2000). Two separate studies have recently shown that the binding of p21 and p27 to the enhancer of Sox2, which encodes an HMG-box transcription factor essential for the maintenance of stem cell identity, is key to its transcriptional silencing so that differentiation can be initiated in NSCs and ESCs (Li et al, 2012a;Marqués-Torrejón et al, 2013). Taking into consideration the extensive involvement of Cdks, cyclins and CKIs in the specification of cell fate (Fig.…”

Sox2 is dispensable for primary melanoma and metastasis formation

“…More recently, Sox2 was revealed by overexpression experiments in genetically engineered mouse models to be a driver of lung SCC 13 . Sox2 was also shown to be critical for the initiation of pituitary gland tumors upon loss of the tumor suppressor p27 or of the retinoblastoma tumor suppressor gene Rb 14,15 . Similarly, Sox2 was required for tumor initiation by murine oligodendroglioma cells and by human glioblastoma cells transplanted into appropriate mouse model systems, in agreement with the reported role of Sox2 in maintaining glioma-initiating cells [16][17][18] .…”