Abstract:Graphical Abstract Highlights d Sash1 signaling in the pulmonary endothelium triggers alveolar cell maturation d Sash1 interacts with b-arrestin1 to activate Akt-eNOS d Endothelial NO stimulates alveolar cell maturation in an sGC-cGMP-dependent manner
“…2 ). This is consistent with other studies that have shown that depletion of SASH1 results in increased cellular proliferation in breast, lung, colon and ovarian cell lines 2 , 3 , 6 , 10 , 17 , 22 . Figure 2 Lung cancer cell lines display increased proliferation following SASH1 depletion.…”
Section: Resultssupporting
confidence: 93%
“…SASH1 can regulate signalling through focal adhesion kinase (FAK) and AKT/PI3K 3 , 10 and promote apoptosis 3 , 8 . SASH1 has also been shown to be required for embryonic development by the regulation of alveolar epithelium cell maturation through nitric oxide signaling 17 .…”
SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.
“…2 ). This is consistent with other studies that have shown that depletion of SASH1 results in increased cellular proliferation in breast, lung, colon and ovarian cell lines 2 , 3 , 6 , 10 , 17 , 22 . Figure 2 Lung cancer cell lines display increased proliferation following SASH1 depletion.…”
Section: Resultssupporting
confidence: 93%
“…SASH1 can regulate signalling through focal adhesion kinase (FAK) and AKT/PI3K 3 , 10 and promote apoptosis 3 , 8 . SASH1 has also been shown to be required for embryonic development by the regulation of alveolar epithelium cell maturation through nitric oxide signaling 17 .…”
SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.
“…Another major change during this period is maturation of AT2 cells, which accelerates secretion of surfactant protein to reduce alveolar surface tension for post-natal air breathing (Young et al, 1991). Endothelial-derived nitric oxide (NO) not only induces maturation of AT1 cells, but also stimulates AKT/eNOS signaling in ECs and upregulates the production of surfactant proteins in AT2 cells (Coulombe et al, 2019). These findings suggest that the EC-derived angiocrine factors (e.g., HGF, NO) play crucial roles in the formation of primitive alveolar septa at this stage.…”
Section: Saccular Stage (E175 To P5 In Mouse 26–36 Weeks In Human)mentioning
Endothelial cells (ECs) constitute small capillary blood vessels and contribute to delivery of nutrients, oxygen and cellular components to the local tissues, as well as to removal of carbon dioxide and waste products from the tissues. Besides these fundamental functions, accumulating evidence indicates that capillary ECs form the vascular niche. In the vascular niche, ECs reciprocally crosstalk with resident cells such as epithelial cells, mesenchymal cells, and immune cells to regulate development, homeostasis, and regeneration in various organs. Capillary ECs supply paracrine factors, called angiocrine factors, to the adjacent cells in the niche and orchestrate these processes. Although the vascular niche is anatomically and functionally well-characterized in several organs such as bone marrow and neurons, the effects of endothelial signals on other resident cells and anatomy of the vascular niche in the lung have not been well-explored. This review discusses the role of alveolar capillary ECs in the vascular niche during development, homeostasis and regeneration.
“…All these findings suggest that the SLY domain is functionally critical for skin pigmentation regulation and may represent a potential mutational hotspot region (5). Recent research indicates that endothelial SASH1 regulates alveolar epithelial cell maturation and promotes pulmonary surfactant production through nitric oxide signaling (25). SASH1 is expressed in a number of human tissues and cells, including whole skin, keratinocytes, fibroblasts and melanocytes (NCBIGene Expression Omnibus; http://www.ncbi.nlm.nih.gov/geo/) (6).…”
The SAM and SH3 domain-containing 1 (SASH1) genes have been identified as the causal genes of dyschromatosis universalis hereditaria (DUH); these genes cause the pathological phenotypes of DUH, and SASH1 variants have been shown to regulate the abnormal pigmentation phenotype in human skin in various genodermatoses. However, investigations into the mutated SASH1 gene have been limited to in vitro studies. In the present study, to recapitulate the molecular pathological phenotypes of individuals with DUH induced by SASH1 mutations, a heterozygous BALB/c mouse model, in which the human SASH1 c.1654 T>G (p. Tyr 551Asp, Y551D) mutation was knocked in was first generated. The in vivo functional experiments on Y551D SASH1 indicated that the increased expression of microphthalmia-associated transcription factor (Mitf) was uniformly induced in the tails of heterozygous BALB/c mice, and an increased quantity of Mitf-positive epithelial cells was also detected. An increased expression of Mitf-and Mitf-positive cells was also demonstrated in the epithelial tissues of Y551D-SASH1 affected individuals. In the present study, Mitf expression was also found to be increased by Y551D SASH1 in vitro. Taken together, these findings indicate that the upregulation of Mitf is the bona fide effector of the Y551D SASH1-mediated melanogenesis signaling pathway in vivo. SASH1 may function as a scaffold molecule for the assembly of a SASH1-Mitf molecular complex to regulate Mitf expression in the cell nucleus and thus to promote the hyperpigmented phenotype in the pathogenesis of DUH and other genodermatoses related to pigment abnormalities.
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