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SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE152010 | GEO | 2021/02/24

REPOSITORIES: GEO

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SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice III

Project description:Exploration of the molecular mechanisms underlying melanotroph tumourigenesis and the role of SOX2 in both SCs and melanotrophs

2021-02-24 | GSE152009 | GEO

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice II

Project description:Characterization of the effects of Sox2 heterozygosity on tumorigenesis in p27-/- pituitary tumors.

2021-02-24 | GSE152008 | GEO

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice I

Project description:Characterization of the initiation and development of pituitary intermediate lobe tumors in p27-/- mice.

2021-02-24 | GSE152007 | GEO

SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in <i>p27</i>-null mice.

Project description:P27, a cell cycle inhibitor, is also able to drive repression of Sox2 This interaction plays a crucial role during development of p27-/- pituitary tumors because loss of one copy of Sox2 impairs tumorigenesis [H. Li et al., Cell Stem Cell 11, 845-852 (2012)]. However, SOX2 is expressed in both endocrine and stem cells (SCs), and its contribution to tumorigenesis in either cell type is unknown. We have thus explored the cellular origin and mechanisms underlying endocrine tumorigenesis in p27-/- pituitaries. We found that pituitary hyperplasia is associated with reduced cellular differentiation, in parallel with increased levels of SOX2 in stem and endocrine cells. Using conditional loss-of-function and lineage tracing approaches, we show that SOX2 is required cell autonomously in p27-/- endocrine cells for these to give rise to tumors, and in SCs for promotion of tumorigenesis. This is supported by studies deleting the Sox2 regulatory region 2 (Srr2), the target of P27 repressive action. Single cell transcriptomic analysis further reveals that activation of a SOX2-dependent MAPK pathway in SCs is important for tumorigenesis. Altogether, our data highlight different aspects of the role of SOX2 following loss of p27, according to cellular context, and uncover an unexpected SOX2-dependent tumor-promoting role for SCs. Our results imply that targeting SCs, in addition to tumor cells, may represent an efficient antitumoral strategy in certain contexts.

| S-EPMC7896314 | biostudies-literature

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice

Project description:SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice

| PRJNA638090 | ENA

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice II

Project description:SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice II

| PRJNA638093 | ENA

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice III

Project description:SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice III

| PRJNA638094 | ENA

SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice I

Project description:SOX2 is required independently in both stem and differentiated cells for pituitary tumor genesis in p27 null mice I

| PRJNA638092 | ENA

p27(Kip1) is required to maintain proliferative quiescence in the adult cochlea and pituitary.

Project description:Cell cycle inhibitors, such as the cyclin-dependent kinase (Cdk) inhibitor proteins and retinoblastoma (Rb) family members, control exit from the cell cycle during the development of a variety of terminally differentiated tissues. It is unclear whether sustained expression of these proteins is required to prevent cell cycle re-entry in quiescent and terminally differentiated cells. The organ of Corti (cochlear sensory epithelium) and pars intermedia (intermediate lobe of the pituitary) are two tissues that share the characteristic of ongoing cell division in mice lacking either the p27(Kip1) Cdk inhibitor, Ink4 proteins, or Rb. Here, we use tamoxifen-inducible mouse models to delete p27(Kip1) in postnatal animals and show this is sufficient to induce proliferation in both the organ of Corti and pars intermedia. Thus, these tissues remain sensitive to the presence of p27(Kip1) even after their developmental exit from the cell cycle. The neonatal cochlea displayed heightened sensitivity to changes in p27(Kip1) expression, with a proliferative response higher than that of constitutive null mice. In adults, the proliferative response was reduced but was accompanied by increased cell survival. In contrast, re-establishment of normal p27(Kip1) expression in animals with established pituitary tumors, in an inducible "knock-on" model, led to cessation of pituitary tumor growth, indicating the cells had maintained their susceptibility to p27-mediated growth suppression. Although restoration of p27(Kip1) did not induce apoptosis, it did lead to resolution of pathological features and normalization of gene expression. Our data underscore the importance of p27(Kip1) expression in the maintenance of cellular quiescence and terminal differentiation.

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p27(Kip1) directly represses Sox2 during embryonic stem cell differentiation.

Project description:The 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.

| S-EPMC3549496 | biostudies-literature

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