LATS2
Serine/threonine-protein kinase LATS2 (EC 2.7.11.1) (Kinase phosphorylated during mitosis protein) (Large tumor suppressor homolog 2) (Serine/threonine-protein kinase kpm) (Warts-like kinase) [KPM]
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The present study was aimed to investigate the expression relationship of Hippo signaling molecules and ovarian germline stem cell (OGSC) markers in the development schedule of OGSCs during ovarian aging in women and mice. The ovaries of 2-month-old mature (normal control) and 12-month-old (physiological ovarian aging) KM mice were sampled, and the ovarian cortex samples of young (postpuberty to 35 years old), middle age (36-50 years old) and menopausal period (51-60 years old) women were obtained with consent. The mice model of pathological ovarian aging was established by intraperitoneal injection of cyclophosphamide/busulfan (CY/BUS). HE staining was used to detect the changes of follicles at different stages, and the localization and expression changes of Hippo signaling molecules and OGSCs related factors (MVH/OCT4) were detected by immunohistochemistry and immunofluorescence staining. Western blot was used to detect the protein expression levels of the major molecules in the Hippo signaling pathway and OGSCs related factors. The results showed that there were not any normal follicles, but a few atresia follicles in the ovaries from physiological and pathological ovarian aging mice. Compared with the normal control mice, both the physiological and pathological ovarian aging mice showed decreased protein expression levels of the main Hippo signaling molecules (pYAP1) and MVH/OCT4; Whereas only the pathological ovarian aging mice showed increased ratio of pYAP1/YAP1. In comparison with the young women, the middle age and menopausal women showed looser structure of ovarian surface epithelium (OSE) and less ovarian cortical cells. The protein expression level of LATS2 in the OSE was the highest in young women, MST1 expression was the lowest in the menopausal period women, and the expression levels of YAP1 and pYAP1 were the highest in middle age women. Compared with the young women, the middle age and menopausal period women exhibited significantly decreased ratio of OSE pYAP1/YAP1, whereas there was no significant difference between them. The expression level of MVH protein in OSE from the young women was significantly higher than those of the middle age and menopausal period women. These results indicate that there is an expression relationship between the main molecules of Hippo signaling pathway and OGSCs related factors, which suggests that Hippo signaling pathway may regulate the expression levels of OGSCs related factors, thus participating in the process of physiological and pathological degeneration of ovarian.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adult
- Aging
- Animals
- Epithelium
- Female
- Humans
- Mice
- Middle Aged
- Octamer Transcription Factor-3
- Oogonial Stem Cells
- Ovarian Follicle
- Ovary
- Phosphoproteins
- Protein-Serine-Threonine Kinases
- Signal Transduction
- Transcription Factors
- Tumor Suppressor Proteins
Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 in hOSEs prevents these cells from natural replicative and YAP1-induced senescence. Most importantly, loss of LATS2 switches ovarian cells from YAP-induced senescence to malignant transformation. Our results demonstrate that LATS2 and YAP1, two major components of the Hippo/YAP signaling pathway, form a negative feedback loop to control YAP1 activity and prevent ovarian cells from malignant transformation. Human cancer genomic data extracted from TCGA datasets further confirm the clinical relevance of our finding.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Animals
- Carcinogenesis
- Cell Cycle Checkpoints
- Cell Lineage
- Cell Proliferation
- Cell Transformation, Neoplastic
- Cells, Cultured
- Cellular Senescence
- Epithelial Cells
- Feedback, Physiological
- Female
- Heterochromatin
- Homeostasis
- Humans
- Mice, Nude
- Models, Biological
- Organ Specificity
- Ovary
- Protein-Serine-Threonine Kinases
- Retinoblastoma Protein
- Signal Transduction
- Transcription Factors
- Tumor Suppressor Proteins
- Viral Proteins
Keywords
- YAP1‐LATS2 feedback loop
- cellular senescence
- the Hippo pathway
- tissue homeostasis
- tumorigenesis