SOX2 Regulates YAP1 to Maintain Stemness and Determine Cell Fate in the Osteo-Adipo Lineage

Seo, Eul Ju; Basu-Roy, Upal; Gunaratne, Preethi H.; Coarfa, Cristian; Lim, Dae–Sik; Basilico, Claudio; Mansukhani, Alka

doi:10.1016/j.celrep.2013.05.029

Cited by 190 publications

(215 citation statements)

References 49 publications

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“…Like cysts in humans with ADPKD (35), kidney cysts in Taz null mice display enhanced Wnt/␤-catenin signaling (65). This provides evidence of cross talk between Wnt and Hippo signaling pathways that has been further validated in other model systems such as colorectal carcinoma and in osteogenesis (30,58). It also provides a potential mechanistic explanation for cyst formation in Taz-null mice.…”

Section: Tubules and Interstitiummentioning

confidence: 77%

Hippo signaling in the kidney: the good and the bad

Wong

Meliambro

Ray

et al. 2016

American Journal of Physiology-Renal Physiology

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The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions.

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Section: Tubules and Interstitiummentioning

confidence: 77%

Hippo signaling in the kidney: the good and the bad

Wong

Meliambro

Ray

et al. 2016

American Journal of Physiology-Renal Physiology

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“…Konsavage et al have reported that β-catenin drives Yap transcription in colorectal cancer cells (35). Yap is also a target of SOX2 and binds β-catenin, thus indirectly dampening Wnt signals that regulate osteoblastic and adipocytic stem cell lineages (36). Given the complexity of the cross-talk between Yap and β-catenin, we did not further examine the mechanism underlying the regulation of β-catenin by Yap in GC cells.…”

Section: Discussionmentioning

confidence: 99%

LKB1 inhibits the proliferation of gastric cancer cells by suppressing the nuclear translocation of Yap and β-catenin

Bian

Cui

et al. 2016

International Journal of Molecular Medicine

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Liver kinase B1 (LKB1) is known to suppress the proliferation, energy metabolism and mesenchymal transition of various cancer cells, and is involved in the regulation of Hippo-Yes-associated protein (Yap) and the Wnt/β-catenin signaling pathways. However, the role of LKB1 in gastric cancer (GC) was not fully understood. Thus, in the present study, we studied LKB1 and found that protein expression (0.37±0.061 vs. 0.59±0.108, P=0.006) and the protein ratio of p-Yap/Yap (0.179±0.085 vs. 0.8±0.126, P=0.001) were reduced in 54 gastric adenocarcinoma (GAC) tissues compared with the matched adjacent non-cancerous tissues, using western blotting and RT-qPCR assays. LKB1 expression was also observed decreased in 109 GAC tissues compared with 54 adjacent non-cancerous tissues (χ2=4.678, P=0.0306), and negatively correlated with the nuclear expression of Yap (r=-0.6997) and β-catenin (r=-0.3510), using immunohistochemical analysis. In GC patients, LKB1 expression was negatively associated with tumor size, tumor infiltration, lymph node metastasis and the TNM stage. LKB1 expression was determined to be positively correlated with longer overall survival of GC patients using Kaplan-Meier analysis (P=0.001). Subsequently, LKB1 expression in human GAC AGS cells was enhanced with a full‑length LKB1 transfection. In vitro and in vivo proliferation was inhibited in LKB1-overexpressing GC cells compared with the control cells. Yap and β-catenin expression were assessed by western blotting and RT-qPCR, and were found to be increased in the cytoplasm but decreased in the nucleus in LKB1-overexpressing GC cells compared with the control cells. The increase in cytoplasmic β-catenin was reversed by the silencing of LKB1 or Yap with shRNAs in LKB1-overexpressing GC cells. Moreover, Yap and β-catenin mRNA were barely altered by LKB1 overexpression. Thus, we concluded that LKB1 expression was reduced in GAC tissues but that it correlated positively with better prognosis for GC patients. LKB1 inhibits the proliferation of GC cells by suppressing the nuclear translocation of Yap and β-catenin.

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“…Also in the postnatal (3-week-old) pituitary, nuclear localization of YAP1 and TAZ was observed in the SOX2 + stem cell niche, and some signals were found scattered in the parenchyma (Lodge et al 2016). As SOX2 has been suggested to exert a stimulatory effect on YAP/TAZ activity in other tissues, directly by promoting Yap1 gene transcription (Seo et al 2013) and indirectly by repressing the Hippo pathway activators neurofibromin 2 (Nf2) and WW domaincontaining protein 1 (Wwc1) (Basu-Roy et al 2015), an upstream regulatory function of SOX2 in the Hippo cascade may also be assumed in the pituitary (stem cells), although this connection has still to be explored.…”

Section: Hippo Pathway: a New Player In Pituitary Stem Cell Regulation?mentioning

confidence: 93%

Pituitary stem cell regulation: who is pulling the strings?

Cox

Roose

Vennekens

et al. 2017

Journal of Endocrinology

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The pituitary gland plays a pivotal role in the endocrine system, steering fundamental processes of growth, metabolism, reproduction and coping with stress. The adult pituitary contains resident stem cells, which are highly quiescent in homeostatic conditions. However, the cells show marked signs of activation during processes of increased cell remodeling in the gland, including maturation at neonatal age, adaptation to physiological demands, regeneration upon injury and growth of local tumors. Although functions of pituitary stem cells are slowly but gradually uncovered, their regulation largely remains virgin territory. Since postnatal stem cells in general reiterate embryonic developmental pathways, attention is first being given to regulatory networks involved in pituitary embryogenesis. Here, we give an overview of the current knowledge on the NOTCH, WNT, epithelial-mesenchymal transition, SHH and Hippo pathways in the pituitary stem/progenitor cell compartment during various (activation) conditions from embryonic over neonatal to adult age. Most information comes from expression analyses of molecular components belonging to these networks, whereas functional extrapolation is still very limited. From this overview, it emerges that the 'big five' embryonic pathways are indeed reiterated in the stem cells of the 'lazy' homeostatic postnatal pituitary, further magnified en route to activation in more energetic, physiological and pathological remodeling conditions. Increasing the knowledge on the molecular players that pull the regulatory strings of the pituitary stem cells will not only provide further fundamental insight in postnatal pituitary homeostasis and activation, but also clues toward the development of regenerative ideas for improving treatment of pituitary deficiency and tumors.

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SOX2 Regulates YAP1 to Maintain Stemness and Determine Cell Fate in the Osteo-Adipo Lineage

Cited by 190 publications

References 49 publications

Hippo signaling in the kidney: the good and the bad

Hippo signaling in the kidney: the good and the bad

LKB1 inhibits the proliferation of gastric cancer cells by suppressing the nuclear translocation of Yap and β-catenin

Pituitary stem cell regulation: who is pulling the strings?

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