scholarly journals DLX Genes: Roles in Development and Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3005
Author(s):  
Yinfei Tan ◽  
Joseph R. Testa
Keyword(s):  
Mouse Model ◽  
Cell Fate ◽  
Active Form ◽  
Homeobox Genes ◽  
Akt Signaling ◽  
Ovarian Cancer Cells ◽  
Cancer Etiology ◽  
Cell Fate Decisions ◽  
Body Patterning ◽  
Dlx Genes

Homeobox genes control body patterning and cell-fate decisions during development. The homeobox genes consist of many families, only some of which have been investigated regarding a possible role in tumorigenesis. Dysregulation of HOX family genes have been widely implicated in cancer etiology. DLX homeobox genes, which belong to the NK-like family, exert dual roles in development and cancer. The DLX genes are the key transcription factors involved in regulating the development of craniofacial structures in vertebrates. The three DLX bigenes have overlapping expression in the branchial arches. Disruption of DLX function has destructive consequences in organogenesis and is associated with certain congenital disorders in humans. The role of DLX genes in oncogenesis is only beginning to emerge. DLX2 diminishes cellular senescence by regulating p53 function, whereas DLX4 has been associated with metastasis in breast cancer. In human ovarian cancer cells, DLX5 is essential for regulating AKT signaling, thereby promoting cell proliferation and survival. We previously implicated Dlx5 as an oncogene in murine T-cell lymphoma driven by a constitutively active form of Akt2. In this mouse model, overexpression of Dlx5 was caused by a chromosomal rearrangement that juxtaposed the Tcr-beta promoter region near the Dlx5 locus. Moreover, transgenic mice overexpressing Dlx5, specifically in immature T-cells, develop spontaneous thymic lymphomas. Oncogenesis in this mouse model involves binding of Dlx5 to the Notch1 and Notch3 gene loci to activate their transcription. Dlx5 also cooperates with Akt signaling to accelerate lymphomagenesis by activating Wnt signaling. We also discuss the fact that human DLX5 is aberrantly expressed in several human malignancies.

Notch1-Induced Delay of Human Hematopoietic Progenitor Cell Differentiation Is Associated With Altered Cell Cycle Kinetics

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 838-848 ◽  
Author(s):  
Nadia Carlesso ◽  
Jon C. Aster ◽  
Jeffrey Sklar ◽  
David T. Scadden
Keyword(s):  
Cell Cycle ◽  
Cord Blood ◽  
Cell Fate ◽  
Active Form ◽  
Hematopoietic Progenitor Cell ◽  
Cell Phenotype ◽  
Cell Cycle Kinetics ◽  
Cell Fate Decisions ◽  
Cd34 Cells ◽  
Altered Cell

Hematopoiesis is a balance between proliferation and differentiation that may be modulated by environmental signals. Notch receptors and their ligands are highly conserved during evolution and have been shown to regulate cell fate decisions in multiple developmental systems. To assess whether Notch1 signaling may regulate human hematopoiesis to maintain cells in an immature state, we transduced a vesicular stomatitis virus G-protein (VSV-G) pseudo-typed bicistronic murine stem cell virus (MSCV)-based retroviral vector expressing a constitutively active form of Notch1 (ICN) and green fluorescence protein into the differentiation competent HL-60 cell line and primary cord blood–derived CD34+ cells. In addition, we observed endogenous Notch1 expression on the surface of both HL-60 cells and primary CD34+ cells, and therefore exposed cells to Notch ligand Jagged2, expressed on NIH3T3 cells. Both ligand-independent and ligand-dependent activation of Notch resulted in delayed acquisition of differentiation markers by HL-60 cells and cord blood CD34+ cells. In addition, primary CD34+cells retained their ability to form immature colonies, colony-forming unit–mix (CFU-mix), whereas control cells lost this capacity. Activation of Notch1 correlated with a decrease in the fraction of HL-60 cells that were in G0/G1phase before acquisition of a mature cell phenotype. This enhanced progression through G1 was noted despite preservation of the proliferative rate of the cells and the overall length of the cell cycle. These findings show that Notch1 activation delays human hematopoietic differentiation and suggest a link of Notch differentiation effects with altered cell cycle kinetics.

scholarly journals MTG16 (CBFA2T3) represses E protein-dependent transcription to regulate colonic secretory cell differentiation, epithelial regeneration, and tumorigenesis

2021 ◽  
Author(s):  
Rachel E. Brown ◽  
Justin Jacobse ◽  
Shruti A. Anant ◽  
Koral M. Blunt ◽  
Bob Chen ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Mouse Model ◽  
Cell Fate ◽  
Protein Interactions ◽  
Protein Function ◽  
Colonic Epithelium ◽  
E Proteins ◽  
Cell Fate Decisions ◽  
Epithelial Regeneration ◽  
E Protein

Aberrant epithelial differentiation and regeneration pathways contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 interaction partners include E box-binding basic helix-loop-helix transcription factors (E proteins). MTG16-deficient mice exhibit worse colitis and increased tumor burden in inflammatory carcinogenesis. In this study, we sought to understand the role of MTG16 in colonic epithelial homeostasis and the mechanisms by which MTG16 protects the epithelium in colitis and CAC. We demonstrated that MTG16 deficiency enabled enteroendocrine cell differentiation from secretory precursor cells at the expense of goblet cells. Transcriptomic analysis implicated dysregulated E protein function in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that disrupts MTG16:E protein complex formation (Mtg16P209T), we established that enteroendocrine:goblet cell balance was dependent on MTG16:E protein interactions and that the shift in lineage allocation was associated with enhanced expression of Neurog3, the central driver of enteroendocrine lineage specification. Furthermore, Mtg16 was upregulated in the previously described Ascl2+, de-differentiating cells that replenish the stem cell compartment in response to colon injury. Mtg16 expression was also increased in dextran sulfate sodium (DSS)-treated mouse colon crypts and in IBD patients compared to unaffected controls. We determined that the effects of MTG16 in regeneration are also dependent on its repression of E proteins, as the colonic epithelium failed to regenerate following DSS-induced injury in our novel mutant mouse model. Finally, we revealed that uncoupling MTG16:E protein interactions contributes to the enhanced tumorigenicity in Mtg16-/- colon in the azoxymethane(AOM)/DSS-induced model of CAC. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colonic differentiation and regeneration.

scholarly journals The Repertoire of Fos and Jun Proteins Expressed during the G1 Phase of the Cell Cycle Is Determined by the Duration of Mitogen-Activated Protein Kinase Activation

1999 ◽  
Vol 19 (1) ◽  
pp. 330-341 ◽  
Author(s):  
Simon J. Cook ◽  
Natasha Aziz ◽  
Martin McMahon
Keyword(s):  
Protein Kinase ◽  
Cell Fate ◽  
Active Form ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Cell Fate Decisions ◽  
Mitogen Activated Protein ◽  
Early Expression ◽  
Fos Expression

ABSTRACT In Rat-1 fibroblasts nonmitogenic doses of lysophosphatidic acid (LPA) stimulate a transient activation of mitogen-activated protein kinase (MAPK), whereas mitogenic doses elicit a sustained response. This sustained phase of MAPK activation regulates cell fate decisions such as proliferation or differentiation, presumably by inducing a program of gene expression which is not observed in response to transient MAPK activation. We have examined the expression of members of the AP-1 transcription factor complex in response to stimulation with different doses of LPA. c-Fos, c-Jun, and JunB are induced rapidly in response to LPA stimulation, whereas Fra-1 and Fra-2 are induced after a significant lag. The expression of c-Fos is transient, whereas the expression of c-Jun, JunB, Fra-1, and Fra-2 is sustained. The early expression of c-Fos can be reconstituted with nonmitogenic doses of LPA, but the response is transient compared to that observed with mitogenic doses. In contrast, expression of Fra-1, Fra-2, and JunB and optimal expression of c-Jun are observed only with doses of LPA which induce sustained MAPK activation and DNA synthesis. LPA-stimulated expression of c-Fos, Fra-1, Fra-2, c-Jun, and JunB is inhibited by the MEK1 inhibitor PD098059, indicating that the Raf-MEK-MAPK cascade is required for their expression. In cells expressing a conditionally active form of Raf-1 (ΔRaf-1:ER), we observed that selective, sustained activation of Raf-MEK-MAPK was sufficient to induce expression of Fra-1, Fra-2, and JunB but, interestingly, induced little or no c-Fos or c-Jun. The induction of c-Fos observed in response to LPA was strongly inhibited by buffering the intracellular [Ca2+]. Moreover, although Raf activation or calcium ionophores induced little c-Fos expression, we observed a synergistic induction in response to the combination of ΔRaf-1:ER and ionomycin. These results suggest that kinetically distinct phases of MAPK activation serve to regulate the expression of distinct AP-1 components such that sustained MAPK activation is required for the induced expression of Fra-1, Fra-2, c-Jun, and JunB. However, in contrast to the case for Fra-1, Fra-2, and JunB, activation of the MAPK cascade alone is not sufficient to induce c-Fos expression, which rather requires cooperation with other signals such as Ca2+mobilization. Finally, the identification of the Fra-1, Fra-2, c-Jun, and JunB genes as genes which are selectively regulated by sustained MAPK activation or in response to activated Raf suggests that they are candidates to mediate certain of the effects of Ras proteins in oncogenic transformation.

scholarly journals Antisense oligonucleotides targeting Notch2 ameliorate the osteopenic phenotype in a mouse model of Hajdu-Cheney syndrome

2020 ◽  
Vol 295 (12) ◽  
pp. 3952-3964 ◽  
Author(s):  
Ernesto Canalis ◽  
Tamar R. Grossman ◽  
Michele Carrer ◽  
Lauren Schilling ◽  
Jungeun Yu
Keyword(s):  
Mouse Model ◽  
Cell Fate ◽  
Antisense Oligonucleotides ◽  
Target Genes ◽  
Skeletal Development ◽  
Subcutaneous Administration ◽  
Mrna Levels ◽  
Developmental Abnormalities ◽  
Cell Fate Decisions ◽  
Related Family

Notch receptors play critical roles in cell-fate decisions and in the regulation of skeletal development and bone remodeling. Gain–of–function NOTCH2 mutations can cause Hajdu-Cheney syndrome, an untreatable disease characterized by osteoporosis and fractures, craniofacial developmental abnormalities, and acro-osteolysis. We have previously created a mouse model harboring a point 6955C→T mutation in the Notch2 locus upstream of the PEST domain, and we termed this model Notch2tm1.1Ecan. Heterozygous Notch2tm1.1Ecan mutant mice exhibit severe cancellous and cortical bone osteopenia due to increased bone resorption. In this work, we demonstrate that the subcutaneous administration of Notch2 antisense oligonucleotides (ASO) down-regulates Notch2 and the Notch target genes Hes-related family basic helix–loop–helix transcription factor with YRPW motif 1 (Hey1), Hey2, and HeyL in skeletal tissue from Notch2tm1.1Ecan mice. Results of microcomputed tomography experiments indicated that the administration of Notch2 ASOs ameliorates the cancellous osteopenia of Notch2tm1.1Ecan mice, and bone histomorphometry analysis revealed decreased osteoclast numbers in Notch2 ASO-treated Notch2tm1.1Ecan mice. Notch2 ASOs decreased the induction of mRNA levels of TNF superfamily member 11 (Tnfsf11, encoding the osteoclastogenic protein RANKL) in cultured osteoblasts and osteocytes from Notch2tm1.1Ecan mice. Bone marrow-derived macrophage cultures from the Notch2tm1.1Ecan mice displayed enhanced osteoclastogenesis, which was suppressed by Notch2 ASOs. In conclusion, Notch2tm1.1Ecan mice exhibit cancellous bone osteopenia that can be ameliorated by systemic administration of Notch2 ASOs.

scholarly journals NF-κB Signaling Is Required for XBP1 (Unspliced and Spliced)-Mediated Effects on Antiestrogen Responsiveness and Cell Fate Decisions in Breast Cancer

2014 ◽  
Vol 35 (2) ◽  
pp. 379-390 ◽  
Author(s):  
Rong Hu ◽  
Anni Warri ◽  
Lu Jin ◽  
Alan Zwart ◽  
Rebecca B. Riggins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Fate ◽  
Active Form ◽  
Dominant Negative ◽  
Cell Fate Decisions ◽  
Mediated Effects ◽  
Survival Pathways ◽  
Estrogen Receptor Positive ◽  
The Unfolded Protein Response

Antiestrogen therapy induces the unfolded protein response (UPR) in estrogen receptor-positive (ER+) breast cancer. X-box binding protein 1 (XBP1), which exists in the transcriptionally inactive unspliced form [XBP1(U)] and the spliced active form [XBP1(S)], is a key UPR component mediating antiestrogen resistance. We now show a direct link between the XBP1 and NF-κB survival pathways in driving the cell fate decisions in response to antiestrogens in ER+breast cancer cells, bothin vitroand in a xenograft mouse model. Using novel spliced and nonspliceable forms of XBP1, we show that XBP1(U) functions beyond being a dominant negative of XBP1(S). Both isoforms regulate NF-κB activity via ERα; XBP1(S) is more potent because it also directly regulates p65/RelA expression. These findings provide new insights into the fundamental signaling activities of spliced and unspliced XBP1 in breast cancer, establish NF-κB to be a mediator of these activities, and identify XBP1 and its splicing to be novel therapeutic targets.

Regulation and Function of NOTCH2 in B-CLL Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1138-1138
Author(s):  
Rainer Hubmann ◽  
Martin Hilgarth ◽  
Susanne Schnabl ◽  
Dita Demirtas ◽  
Josef D. Schwarzmeier ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Target Gene ◽  
Active Form ◽  
Lymphocytic Leukemia ◽  
B Cell Differentiation ◽  
Cell Fate Decisions ◽  
Mutational Status ◽  
And Function

Abstract B-cell chronic lymphocytic leukemia (B-CLL) represents a clonal expansion of self-reactive CD5+ B-lymphocytes which seems to be resistant to apoptosis in vivo. One of the characteristics of B-CLL lymphocytes is the high expression of the B-cell differentiation/activation marker CD23 which we recently identified as a target gene for NOTCH2 signaling. NOTCH2 is implicated in the development/homeostasis of murine CD5+ (B-1a) B-cells, suggesting a function for human NOTCH2 in B-CLL leukemogenesis. Here we show that peripheral B-CLL lymphocytes overexpress a transcriptionally active form of NOTCH2 (N2IC) irrespective of their prognostic marker profile (ie. IgVH mutational status, CD38 expression, and cytogenetics). Although the majority of unstimulated B-CLL samples downregulate their N2IC activity in vitro, DNA-bound N2IC complexes could be maintained by the protein kinase C (PKC) activator TPA (12-O-tetradecanoylphorbol 13-acetate) accompanied by an upregulation of the NOTCH2 target gene CD23 and increased B-CLL cell viability. These effects are sensitive to the PKC-δ selective inhibitor Rottlerin. In 80% of B-CLL cases, NOTCH2 signaling was found to be resistant to the γ-secretase inhibitors (GSI’s) Dapt and compound E, indicative for the expression of truncated forms of NOTCH2 which do not require γ-secretase for processing and function. Inhibition of NOTCH2 either by Dapt in GSI sensitive B-CLL cases or, more specifically, by RNA interference downregulates CD23 expression on the mRNA and protein level and sensitizes B-CLL cells for apoptosis. Since self-reactive B-cells are normally eliminated either by chronic (anergy) or apoptotic (negative selection) B-cell receptor (BCR) signaling, we asked whether NOTCH2 modulates B-cell fate decisions triggered by the BCR. For this reason, we stably transduced the human B-cell line BL41 with constitutive active forms of NOTCH2 and found that NOTCH2 inhibits BCR mediated apoptosis induced by surface-IgM cross-linking. In summary, the data demonstrate that NOTCH2 signaling is deregulated in B-CLL cells and might be critically involved in the PKC-dependent maintenance of their malignant phenotype.

scholarly journals Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage

2020 ◽  
Author(s):  
Sophie Colombo ◽  
Valérie Petit ◽  
Roselyne Y Wagner ◽  
Delphine Champeval ◽  
Ichiro Yajima ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Cell Fate ◽  
Active Form ◽  
Cell Lineage ◽  
Cell Fate Decisions ◽  
Schwann Cell Development ◽  
Summary Statement ◽  
Schwann Cell Precursors ◽  
Canonical Wnt

AbstractThe canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates Mitf-M transcription, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, while a small number of second wave melanocytes is derived from Schwann-cell precursors (SCPs). We investigated the influence of β-catenin in the development of melanocytes of the first and second waves by generating mice expressing a constitutively active form of β-catenin in cells expressing tyrosinase. Constitutive activation of β-catenin did not affect the development of truncal melanoblasts, but led to a marked hyperpigmentation of the paws. By activating β-catenin at various stages of development (E8.5-E11.5), we showed that the activation of β-catenin in bipotent SCPs favored melanoblast specification at the expense of Schwann cells in the limbs within a specific temporal window. In addition, hyperactivation of the Wnt/β-catenin pathway repressed FoxD3 expression, which is necessary for Schwann cell development, through Mitf-M activation. In conclusion, β-catenin overexpression promotes SCP cell-fate decisions towards the melanocyte lineage.Summary statementActivation of β-catenin in bipotent Schwann-cell precursors during a specific developmental window, induces MITF and represses FoxD3 to promote melanoblast cell fate at the expense of Schwann cells in limbs.

Dynamic Expression of Id2 Determines Cell Fate Decisions in Multipotent Hematopoietic Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2369-2369
Author(s):  
Jonathan R Keller ◽  
Ming Ji ◽  
Huajie Li ◽  
Serguei V Kozlov ◽  
Lino Tessarollo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mouse Model ◽  
Nk Cells ◽  
Cell Fate ◽  
Expression Profile ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Developmental Potential ◽  
Cell Fate Decisions ◽  
Lymphoid Development

Abstract Abstract 2369 Inhibitor of DNA binding protein-2 (Id2) is a member of the helix-loop-helix family of transcriptional regulators that is required for the normal development of natural killer (NK) cells, dendritic cells, B cells and erythrocytes. However, little is known about the expression and function of Id2 in hematopoietic stem and progenitor cells (HSPC). Recent evidence suggests that cell fate is resolved in HSPC by regulating the levels transcription factor expression. Therefore, to determine if Id2 functions in cell fate decisions, and in which progenitor populations these decisions are made, we generated an Id2-EYFP reporter mouse model and validated that EYFP accurately reflected Id2 expression. Using this model we mapped Id2 expression levels in purified HSPC and their differentiated progeny. Id2 is highly expressed in differentiated neutrophils, dendritic cells and NK cells, but is suppressed during erythroid development. Id2 expression is dynamically regulated during lymphoid development, with high levels of Id2 expression in lymphoid progenitors that are down regulated during the early stages of T cell (DN2-DN4) and B cell (Pre-B) differentiation. Id2 is then up-regulated and highly expressed in CD4+CD8+ and single positive CD4 and CD8 thymocytes, suggesting that Id2 may have novel functions in differentiated T cells and in neutrophils. Id2 is expressed in HSC and multi-potent progenitors (MPP), is decreased in common myeloid progenitors (CMP), and further decreased in myeloid/erythroid progenitors (MEP), but increased in granulocyte/macrophage progenitors (GMP). We also observed a range of Id2 expression within purified HSPC, suggesting that the levels of Id2 expression in purified HSC, MPP and CMP may correlate with potential of these progenitors for myeloid, erythroid and lymphoid development. To investigate this, CMP Id2-hi and CMP-Id2-low expressing cells were sorted and evaluated for differentiation potential in vitro. CMP-Id2-hi cells showed greatly increased myeloid developmental potential compared to the CMP-Id2-low cells as indicated by flow cytometry and growth in soft agar. Gene expression profiles confirmed these results and showed that the CMP-Id2-hi cell expression profile correlated with the expression profile of GMP, while the CMP-Id2-lo cells showed an expression profile that resembled MEP. Based on these observations we anticipate that MPP-Id2-hi and MPP-Id2-lo cells will show differences in myeloid and lymphoid potential. The expression of Id2 in primitive HSPC suggested that Id2 may be required for the maintenance and fate of HSC. Using the Id2−/− mouse model, we discovered that Id2−/− bone marrow cells have impaired ability to rescue mice after serial transplantation, suggesting that Id2 is required for HSC self-renewal. Competitive repopulation assays showed that Id2−/− HSC have diminished repopulation potential. Thus, these data suggest that Id2 is required for the self-renewal of HSC, and that changes in the levels of Id2 expression are associated with cell fate determination of HSPC. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Notch1 Deficiency Induces Tumor Cell Accumulation Inside the Bronchiolar Lumen and Increases TAZ Expression in an Autochthonous KrasLSL-G12V Driven Lung Cancer Mouse Model

2021 ◽  
Vol 27 ◽  
Author(s):  
Lydia Meder ◽  
Alexandra Florin ◽  
Luka Ozretić ◽  
Marieke Nill ◽  
Mirjam Koker ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Model ◽  
Notch Signaling ◽  
Cell Fate ◽  
Human Lung Cancer ◽  
Lung Carcinogenesis ◽  
Lung Carcinomas ◽  
Cell Fate Decisions ◽  
Lung Adenocarcinomas

Purpose: Abrogation of Notch signaling, which is pivotal for lung development and pulmonary epithelial cell fate decisions was shown to be involved in the aggressiveness and the differentiation of lung carcinomas. Additionally, the transcription factors YAP and TAZ which are involved in the Hippo pathway, were recently shown to be tightly linked with Notch signaling and to regulate the cell fate in epidermal stem cells. Thus, we aim to elucidate the effects of conditional Notch1 deficiency on carcinogenesis and TAZ expression in lung cancer.Methods: We investigated the effect of conditional Cre-recombinase mediated Notch1 knock-out on lung cancer cells in vivo using an autochthonous mouse model of lung adenocarcinomas driven by KrasLSL-G12V and comprehensive immunohistochemical analysis. In addition, we analyzed clinical samples and human lung cancer cell lines for TAZ expression and supported our findings by publicly available data from The Cancer Genome Atlas (TCGA).Results: In mice, we found induction of papillary adenocarcinomas and protrusions of tumor cells from the bronchiolar lining upon Notch1 deficiency. Moreover, the mutated Kras driven lung tumors with deleted Notch1 showed increased TAZ expression and focal nuclear translocation which was frequently observed in human pulmonary adenocarcinomas and squamous cell carcinomas of the lung, but not in small cell lung carcinomas. In addition, we used data from TCGA to show that putative inactivating NOTCH1 mutations co-occur with KRAS mutations and genomic amplifications in lung adenocarcinomas.Conclusion: Our in vivo study provides evidence that Notch1 deficiency in mutated Kras driven lung carcinomas contributes to lung carcinogenesis in a subgroup of patients by increasing TAZ expression who might benefit from TAZ signaling blockade.

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