Evaluation of the roles of Lats1 and Lats2 in the development of the Müllerian ducts
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PROVIDER: PRJNA560338 | ENA |
REPOSITORIES: ENA
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Project description:Development of the female tract results from the carefull coordination of numerous signaling pathways. Here, we evaluated the role of hippo pathway in the development of the female reproductive tract. We used microarray to compare the gene expression changes observed in the Müllerian ducts of E17.5 mice embryos between control group and experimental (mutant) group bearing a conditional deletion of both (conjoint) Lats1 and Lats2 using the Amhr2cre strain.
2019-10-10 | GSE135855 | GEO
Project description:Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacological activation of PPARg elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anti-cancer treatments.
2018-10-28 | GSE116817 | GEO
Project description:Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacological activation of PPARg elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anti-cancer treatments.
2018-10-28 | GSE116816 | GEO
Project description:We characterized the transcriptomes of both primary tumors and lung metastases tha developed in mice following deletion of Lats1 and Lats2 from Slc34a1-expressing cells as well as tumors arising from kidney allografts of and immortalized Lats1-/-;Lats2-/- cell line derived from the renal papilla.
2021-01-15 | GSE164879 | GEO
Project description:RNA-sequencing results with in vitro cultured control and Lats1/2 deficient hepatoblasts, in vitro differentiated control and Lats1/2 deficient hepatocytes and biliary epithelial cells To investigate changes in gene expression by loss of Lats1 and Lats2 during hepatocyte or biliary epithelial cell differentiation, we performed multiplex RNA-sequecing with in vitro cultured hepatoblasts, in vitro differentiated hepatocytes and biliary epithelial cells
2016-06-29 | E-GEOD-71873 | biostudies-arrayexpress
Project description:Autophagy perturbation represents an emerging therapeutic strategy in cancer. The mammalian Hippo pathway is an evolutionary conserved tumor suppressive network, where the kinases LATS1/2 phosphorylate and inactivate oncogenic YAP/TAZ. Here, we demonstrated a pro-survival role of LATS1, but not LATS2, in hepatocellular carcinoma cells in response to sorafenib, a standard care of advanced HCC. Transcriptomic analysis revealed a restrictive role of LATS1 in autophagy regulation in HCC cells. Further, we found that the autophagy regulation by LATS1 was independent of its kinase activity. Instead, LATS1 stabilized autophagy core-machinery component Beclin 1 via promoting a non-canonical form of K27-linked ubiquitination, and consequently, inactive Beclin 1 self-dimer, in a E3 ligase NEDD4 dependent manner. Our study highlights a functional diversity between LATS1 and LATS2 and uncovers a scaffolding role of LATS1 in mediating a cross-talk between Hippo signalling and autophagy in HCC and therapy response.
2019-11-13 | GSE117116 | GEO
Project description:Chromatin modifying activities for construction of appropriate epigenetic landscapes by polycomb repressive complex 2 (PRC2) play an essential role in development and tumorigenesis. However, the spatiotemporal mechanisms by which PRC2 achieves diverse epigenomes for specific tissue or cellular contexts remain poorly understood. Here, we discovered that LATS2 knockout causes dysregulation of PRC2 and subsequent transcriptome changes for differentiation in both mouse and human cells. LATS2 depletion dependent dysregulation of PRC2 also effects H3K4me3 and forms negative feedback loop for maintenance of PRC2. Further analyses reveal that LATS2 on chromatin binds to EZH2 and LATS2 has ability to phosphorylate PRC2 in vitro. These LATS2 dependent H3K27me3 targets are highly induced during neurogenesis, and statistical analysis of glioblastoma multiforme reveals that LATS2-high cases show more dedifferentiated transcriptome and poor prognosis with silencing of H3K27me3 targets. These observations suggest that LATS2-mediated epigenome coordination is pivotal for development and disease, including cancer.
2016-07-26 | GSE63533 | GEO
Project description:Lats1 and Lats2 are the mediators of the Hippo pathway that regulates tissue growth and proliferation. Lats1 and Lats2 kinases share 85% sequence identity in the kinase domain. However, their non-kinase regions at the N-terminus are distinct except for Lats conserved domain 1 (LCD1) and LCD2, suggesting that their N-terminal regions are important for Lats1/2-specific functions. In this study, we generated Lats1 knockout mice disrupting the N-terminal region containing LCD1 (Lats1M-NM-^TN/M-NM-^TN). We show that some Lats1M-NM-^TN/M-NM-^TN mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1M-NM-^TN/M-NM-^TN mice displayed drastic defects in mitosis, showing enhanced centrosome overduplication, chromosomal misalignment, multipolar spindle formation, chromosome bridging, and cytokinesis failure. Moreover, they displayed accelerated cell cycle and cell growth bypassing a cell-cell contact inhibition like tumor cells, and exhibited anchorage independent growth. Indeed, Lats1M-NM-^TN/M-NM-^TN MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than ordinary cancer cells. Furthermore, Yap, the key transcriptional co-activator in the Hippo pathway, was overexpressed and retained stable in Lats1M-NM-^TN/M-NM-^TN MEFs under high cell density, and expression of Lats2 mRNA were down-regulated. Total RNAs were extracted from MEFs under high or low cell density using miRNeasy extraction kit (Qiagen). A Dye-swapped experiment was performed by hybridizing complimentary RNA (cRNA) labeled with either Cyanine (Cy) -3 or Cy-5 (Perkin-Elmer) onto Whole Mouse Genome Oligo Microarray (G4122F; Agilent Technologies). Co-hybridizations were performed and data from Cy3 or Cy5 channels were analyzed as normalized signal intensities rather than as log ratios corresponding to each array.
2012-12-17 | E-GEOD-37871 | biostudies-arrayexpress
Project description:Chromatin modifying activities for construction of appropriate epigenetic landscapes by polycomb repressive complex 2 (PRC2) play an essential role in development and tumorigenesis. However, the spatiotemporal mechanisms by which PRC2 achieves diverse epigenomes for specific tissue or cellular contexts remain poorly understood. Here, we discovered that LATS2 knockout causes dysregulation of PRC2 and subsequent transcriptome changes for differentiation in both mouse and human cells. LATS2 depletion dependent dysregulation of PRC2 also effects H3K4me3 and forms negative feedback loop for maintenance of PRC2. Further analyses reveal that LATS2 on chromatin binds to EZH2 and LATS2 has ability to phosphorylate PRC2 in vitro. These LATS2 dependent H3K27me3 targets are highly induced during neurogenesis, and statistical analysis of glioblastoma multiforme reveals that LATS2-high cases show more dedifferentiated transcriptome and poor prognosis with silencing of H3K27me3 targets. These observations suggest that LATS2-mediated epigenome coordination is pivotal for development and disease, including cancer. Four conditions (mock, siLATS1, siLATS2 and siLATS1/LATS2) were analyzed by Agilent Whole Human Genome Microarray 4x44K v2 (eArray) one color experiments, resulting in four individual microarrays.
2016-07-26 | E-GEOD-63533 | biostudies-arrayexpress
Project description:Lats1 and Lats2 are the mediators of the Hippo pathway that regulates tissue growth and proliferation. Lats1 and Lats2 kinases share 85% sequence identity in the kinase domain. However, their non-kinase regions at the N-terminus are distinct except for Lats conserved domain 1 (LCD1) and LCD2, suggesting that their N-terminal regions are important for Lats1/2-specific functions. In this study, we generated Lats1 knockout mice disrupting the N-terminal region containing LCD1 (Lats1ΔN/ΔN). We show that some Lats1ΔN/ΔN mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1ΔN/ΔN mice displayed drastic defects in mitosis, showing enhanced centrosome overduplication, chromosomal misalignment, multipolar spindle formation, chromosome bridging, and cytokinesis failure. Moreover, they displayed accelerated cell cycle and cell growth bypassing a cell-cell contact inhibition like tumor cells, and exhibited anchorage independent growth. Indeed, Lats1ΔN/ΔN MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than ordinary cancer cells. Furthermore, Yap, the key transcriptional co-activator in the Hippo pathway, was overexpressed and retained stable in Lats1ΔN/ΔN MEFs under high cell density, and expression of Lats2 mRNA were down-regulated.
2012-12-17 | GSE37871 | GEO