ORCID Profile
0000-0002-4631-174X
Current Organisation
SciLifeLab
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Publisher: Oxford University Press (OUP)
Date: 09-12-2014
DOI: 10.1093/NAR/GKU1293
Publisher: Springer Science and Business Media LLC
Date: 25-04-2022
DOI: 10.1038/S41467-022-29912-2
Abstract: There is le support for developmental regulation of glioblastoma stem cells. To examine how cell lineage controls glioblastoma stem cell function, we present a cross-species epigenome analysis of mouse and human glioblastoma stem cells. We analyze and compare the chromatin-accessibility landscape of nine mouse glioblastoma stem cell cultures of three defined origins and 60 patient-derived glioblastoma stem cell cultures by assay for transposase-accessible chromatin using sequencing. This separates the mouse cultures according to cell of origin and identifies three human glioblastoma stem cell clusters that show overlapping characteristics with each of the mouse groups, and a distribution along an axis of proneural to mesenchymal phenotypes. The epigenetic-based human glioblastoma stem cell clusters display distinct functional properties and can separate patient survival. Cross-species analyses reveals conserved epigenetic regulation of mouse and human glioblastoma stem cells. We conclude that epigenetic control of glioblastoma stem cells primarily is dictated by developmental origin which impacts clinically relevant glioblastoma stem cell properties and patient survival.
Publisher: Elsevier
Date: 2018
Publisher: Wiley
Date: 20-12-2012
DOI: 10.1002/JCP.24229
Abstract: Epithelial plasticity characterizes embryonic development and diseases such as cancer. Epithelial-mesenchymal transition (EMT) is a reversible and guided process of plasticity whereby embryonic or adult epithelia acquire mesenchymal properties. Multiple signaling pathways control EMT, and the transforming growth factor β (TGFβ) pathway plays a central role as its inducer. Here, we analyzed the role of the tumor suppressor protein p53 in TGFβ-induced EMT in a well-established mammary epithelial cell model. We found that diploid NMuMG mammary cells bi-allelically express a wild type and a missense mutant (R277C) form of p53. Global reduction of both forms of p53 led to an enhanced EMT response to TGFβ. Conversely, stabilization of wild type p53 using the compound nutlin had a negative impact on EMT. After silencing both p53 forms, rescue experiments using either wild type or R277C mutant p53 revealed that wild type p53 inhibited, whereas the R277C mutant did not significantly affect, the TGFβ-driven EMT response. Under serum-free culture conditions, silencing of total p53 levels led to higher numbers of mammospheres characterized by larger size. Rescue of the silenced endogenous p53 with R277C mutant p53, in contrast, suppressed both size and numbers of the mammospheres. This work proposes that wild type p53 controls the efficiency by which mammary epithelial cells undergo EMT in response to TGFβ.
Publisher: The Company of Biologists
Date: 15-02-2008
DOI: 10.1242/JCS.013557
Abstract: Rho GTPases and their downstream effectors regulate changes in the actin cytoskeleton that underlie cell motility and adhesion. They also participate, with RhoA, in the regulation of gene transcription by activating serum response factor (SRF)-mediated transcription from the serum response element (SRE). SRF-mediated transcription is also promoted by several proteins that regulate the polymerization or stability of actin. We have previously identified a family of PP2C phosphatases, POPXs, which can dephosphorylate the CDC42/RAC-activated kinase PAK and downregulate its enzymatic and actin cytoskeletal activity. We now report that POPX2 interacts with the formin protein mDia1 (DIAPH1). This interaction is enhanced when mDia1 is activated by RhoA. The binding of POPX2 to mDia1 or to an mDia-containing complex greatly decreases the ability of mDia1 to activate transcription from the SRE. We propose that the interaction between mDia1 and POPX2 (PPM1F) serves to regulate both the actin cytoskeleton and SRF-mediated transcription, and to link the CDC42/RAC1 pathways with those of RhoA.
Publisher: Informa UK Limited
Date: 17-11-2014
Publisher: Springer Science and Business Media LLC
Date: 16-02-2018
Publisher: Elsevier BV
Date: 03-2012
Publisher: Elsevier BV
Date: 02-2002
DOI: 10.1016/S0960-9822(02)00652-8
Abstract: The Rho GTPases are involved in many signaling pathways and cellular functions, including the organization of the actin cytoskeleton, regulation of transcription, cell motility, and cell ision. The p21 (Cdc42/Rac)-activated kinase PAK mediates a number of biological effects downstream of these Rho GTPases (reviewed by [1]). The phosphorylation state of mammalian PAK is highly regulated: upon binding of GTPases, PAK is potently activated by autophosphorylation at multiple sites, although the mechanisms of PAK downregulation are not known. We now report two PP2C-like serine/threonine phosphatases (POPX1 and POPX2) that efficiently inactivate PAK. POPX1 was isolated as a binding partner for the PAK interacting guanine nucleotide exchange factor PIX. The dephosphorylating activity of POPX correlates with an ability to block the in vivo effects of active PAK. Consonant with these effects on PAK, POPX can also inhibit actin stress fiber breakdown and morphological changes driven by active Cdc42(V12). The association of the POPX phosphatases with PAK complexes may allow PAK to cycle rapidly between active and inactive states it represents a unique regulatory component of the signaling pathways of the PAK kinase family.
Publisher: Elsevier BV
Date: 11-2008
Publisher: Wiley
Date: 10-01-2019
DOI: 10.1002/PATH.5186
Abstract: Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient-derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.CANLET.2011.12.009
Abstract: Reactive oxygen species (ROS), the most prominent free radicals produced in cells, can have both beneficial and detrimental effects on them. Many genes are known to be involved in ROS regulation. P53 inducible gene 3 (PIG3 or TP53I3) was identified in an analysis of genes induced by p53 before the onset of apoptosis. It is a widely conserved gene between many species. Until now it has been shown to exert two disparate cellular roles. The first is that of ROS producer linked to p53 induced apoptosis. In this context, it exhibits a NADPH dependent reductase activity with orthoquinones. The second is that of a component of the DNA damage response pathway. While it is considered as a p53 dependent pro-apoptotic gene, it is rarely affected in cancer. This data does not support an anti-tumor activity. In the present review we present and discuss aspects on the regulation and function of this factor and how it is implicated in cancer. We conclude by proposing that PIG3 may possibly have a role in cancer cell survival.
Location: Sweden
No related grants have been discovered for E-Jean Tan.