Hhex promotes NK cell homeostasis by repressing BIM-dependent apoptosis
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ABSTRACT:
PROVIDER: PRJNA589086 | ENA |
REPOSITORIES: ENA
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Project description:Hhex encodes a homeobox transcriptional regulator that plays a key role in embryonic development and hematopoiesis. Hhex is highly expressed in NK cells and germline deletion of Hhex results in significant defects in lymphoid development, including NK cells. However, whether Hhex is intrinsically required throughout NK cell development or for NK cell function remains unknown. To investigate this, we generated mice that specifically lack Hhex in NK cells. Hhex was intrinsically required for NK cell homeostasis, while NK cell differentiation, IL-15 responsiveness and cytotoxic function were largely normal in the absence of Hhex. Unexpectedly, increased IL-15 availability failed to rescue Hhex-deficient NK cell homeostasis, suggesting that Hhex regulates developmental pathways extrinsic to those dependent on IL-15. Gene expression and functional genetic approaches revealed that Hhex promoted NK cell survival by repressing BIM expression, a key apoptotic mediator in NK cells. This study identifies Hhex as a novel transcription factor essential for NK cell biology.
2020-11-12 | GSE140284 | GEO
Project description:Hhex encodes a homeobox transcriptional regulator important for embryonic development and hematopoiesis. Hhex is highly expressed in NK cells and its germline deletion results in significant defects in lymphoid development, including NK cells. To determine if Hhex is intrinsically required throughout NK cell development or for NK cell function, we generated mice that specifically lack Hhex in NK cells. NK cell numbers was dramatically reduced, while NK cell differentiation, IL-15 response and function at the cellular level remained largely normal in the absence of Hhex. Increased IL-15 availability failed to fully reverse NK lymphopenia following conditional Hhex deletion, suggesting that Hhex regulates developmental pathways extrinsic to those dependent on IL-15. Gene expression and functional genetic approaches revealed that Hhex regulates NK cell survival by repressing expression of the key apoptotic mediator, BIM. These data implicates Hhex as a novel transcription factor essential for NK cell homeostasis and immunity.
2020-08-11 | GSE155957 | GEO
Project description:Hhex promotes NK cell homeostatis by repressing BIM-dependent apoptosis
| PRJNA656206 | ENA
Project description:C-MYC (henceforth MYC) is one of the most frequently overexpressed oncogenes in human cancer and even modestly deregulated MYC expression can initiate ectopic proliferation in many post-mitotic, terminally differentiated cell types in vivo. Metazoan organisms have consequently evolved a number of mechanisms to counteract MYC's oncogenic potential, of which apoptosis is arguably the best understood. However, the mechanisms through which MYC induces apoptosis remains controversial, with some studies implicating p19ARF-mediated stabilization of p53, followed by induction of pro-apoptotic BH3 family member NOXA and PUMA, while others argue for more direct regulation of BH3 proteins, especially BIM. The debate likely stems from the use of different experimental systems, modes of perturbation, and quite possibly different levels of MYC expression. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used tumoricidal chemotherapeutic, Doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined. MYC-ER ChIP-Seq with HC20 anti-ER antibody in MCF10A cells performed on an Illumina IIx Genome Analyzer.
2015-05-18 | E-GEOD-59001 | biostudies-arrayexpress
Project description:Here we showed that SOX7 was significantly downregulated in different cancer types, especially in lung and breast cancers. Low expression of SOX7 was associated with advanced stage of cancer with shorter overall survival. Cancer cells with loss of SOX7 promoted cell survival and colony formation, suppressed cellular apoptosis and produced a drug resistant phenotype against a variety of chemo/targeting therapeutic agents. Mechanistically, SOX7 induced cellular apoptosis through upregulation of genes associated with both P38 and apoptotic signaling pathway, as well as preventing the proteasome mediated degradation of pro-apoptotic protein BIM. Treatment of either a proteasome inhibitor MG132 or bortezomib, or with a p-ERK/MEK inhibitor U0126 attenuate the SOX7 promoted BIM degradation.
2022-05-08 | GSE130917 | GEO
Project description:C-MYC (henceforth MYC) is one of the most frequently overexpressed oncogenes in human cancer and even modestly deregulated MYC expression can initiate ectopic proliferation in many post-mitotic, terminally differentiated cell types in vivo. Metazoan organisms have consequently evolved a number of mechanisms to counteract MYC's oncogenic potential, of which apoptosis is arguably the best understood. However, the mechanisms through which MYC induces apoptosis remains controversial, with some studies implicating p19ARF-mediated stabilization of p53, followed by induction of pro-apoptotic BH3 family member NOXA and PUMA, while others argue for more direct regulation of BH3 proteins, especially BIM. The debate likely stems from the use of different experimental systems, modes of perturbation, and quite possibly different levels of MYC expression. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used tumoricidal chemotherapeutic, Doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined.
2015-05-18 | GSE59001 | GEO
Project description:SOX7 regulates MAPK/ERK-BIM mediated apoptosis in cancer cells
| PRJNA541940 | ENA
Project description:HHEX KD led to the differential expression of genes in pathway or cellular function related to cell proliferation and anti-apoptosis
2022-11-03 | GSE216850 | GEO
Project description:Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. De-repression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance “free” cellular BIM levels both led to re-sensitization of mesenchymal EGFR mutant cancers to EGFR inhibitors. This relationship between EMT and loss of BIM is not restricted to EGFR mutant lung cancers as it was also observed in KRAS mutant lung cancers and large datasets including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies.
2018-01-01 | GSE106896 | GEO
Project description:The Hematopoietically-expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia (AML) indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16Ink4a and p19Arf. However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors. This enabled serial replating of myeloid progenitors, leading to the rapid establishment of IL-3-dependent promyelocytic cell lines. Use of a Hhex-ERT2 fusion protein demonstrated that continuous nuclear Hhex is required for transformation, and structure function analysis demonstrated a requirement of the DNA binding and N-terminal repressive domains of Hhex for promyelocytic transformation. This included the N-terminal Pml interaction domain, although deletion of Pml failed to prevent Hhex-induced promyelocyte transformation, implying other critical partners. Furthermore, deletion of p16Ink4a or p19Arf did not promote promyelocyte transformation, indicating that repression of distinct Hhex target genes is required for this process. Indeed, transcriptome analysis showed that Hhex overexpression resulted in repression of several myeloid developmental genes. To test potential for Hhex overexpression to contribute to leukemic transformation, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common b subunit (bcV449E). The resultant cell lines resulted in a rapid promyelocytic leukemia in vivo. Thus Hhex overexpression can contribute to myeloid leukemia via multiple mechanisms including differentiation blockade and enabling epigenetic repression of the Cdkn2a locus.
2018-01-30 | GSE109793 | GEO