scholarly journals IRES-mediated translation of the pro-apoptotic Bcl2 family member PUMA

Translation ◽  
2013 ◽  
Vol 1 (1) ◽  
pp. e24391
Author(s):  
Atossa Shaltouki ◽  
Terri J. Harford ◽  
Anton A. Komar ◽  
Crystal M. Weyman
Keyword(s):  
Family Member ◽  
Bcl2 Family ◽  
Bcl2 Family Member

scholarly journals RETRACTED ARTICLE: Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation

2016 ◽  
Vol 7 (10) ◽  
pp. e2419-e2419 ◽  
Author(s):  
Tahereh Javaheri ◽  
Zahra Kazemi ◽  
Jan Pencik ◽  
Ha TT Pham ◽  
Maximilian Kauer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Family Member ◽  
Cell Cycle Progression ◽  
Bone Development ◽  
Bone Cancer ◽  
Growth Factor Signaling ◽  
Cycle Progression ◽  
Bcl2 Family ◽  
Immunocompromised Mice ◽  
Bcl2 Family Member

Abstract Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer.

scholarly journals The muscle regulatory transcription factor MyoD participates with p53 to directly increase the expression of the pro-apoptotic Bcl2 family member PUMA

APOPTOSIS ◽  
2017 ◽  
Vol 22 (12) ◽  
pp. 1532-1542 ◽  
Author(s):  
Terri J. Harford ◽  
Greg Kliment ◽  
Girish C. Shukla ◽  
Crystal M. Weyman
Keyword(s):  
Transcription Factor ◽  
Family Member ◽  
Bcl2 Family ◽  
Bcl2 Family Member

Placement of the BCL2 Family Member BAX in the Death Pathway of Sympathetic Neurons Activated by Trophic Factor Deprivation

1998 ◽  
Vol 152 (1) ◽  
pp. 150-162 ◽  
Author(s):  
Thomas L. Deckwerth ◽  
Rachael M. Easton ◽  
C.Michael Knudson ◽  
Stanley J. Korsmeyer ◽  
Eugene M. Johnson
Keyword(s):  
Family Member ◽  
Sympathetic Neurons ◽  
Trophic Factor ◽  
Bcl2 Family ◽  
Trophic Factor Deprivation ◽  
Bcl2 Family Member

BCL2 Splice Isoform Switching Promotes Leukemia Stem Cell Survival and Sensitivity to a Novel Pan BCL2 Inhibitor

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2735-2735 ◽  
Author(s):  
Daniel Goff ◽  
Kristen M Smith ◽  
Alice Y Shih ◽  
Angela Court-Recart ◽  
Anil Sadarangani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cord Blood ◽  
Family Member ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Bcl2 Family ◽  
Tki Resistance ◽  
Splice Isoform ◽  
Bcl2 Family Member

Abstract Abstract 2735 Leukemia stem cells (LSC) play a crucial role in the development and progression of chronic myeloid leukemia (CML). Although BCR-ABL targeted tyrosine kinase inhibitors (TKI), such as dasatinib, can eradicate the majority of CML cells, they frequently fail to eliminate the dormant, niche-resident LSC that are hypothesized to drive CML relapse. Cumulative evidence from CML cell lines and CD34+ primary patient cells suggests that increased expression of pro-survival BCL2 family members contributes to TKI resistance and CML progression. However there is a relative dearth of data on BCL2 family expression in primary CML LSC and on the role of these proteins in TKI resistance in selective niches. Full transcriptome RNA sequencing revealed that LSC switch from pro-apoptotic to pro-survival BCL2 family member splice isoform expression during progression from chronic phase to blast crisis CML. Using splice isoform-specific qRT-PCR, we identified overrepresentation of long (pro-survival) compared with short (pro-apoptotic) MCL1, BCLX, and BCL2 isoforms in blast crisis LSC compared with chronic phase and normal progenitors. Following intrahepatic transplantation of blast crisis LSC into neonatal RAG2−/−gc−/− mice, LSC engrafted in the marrow niche were quiescent, were dasatinib resistant and upregulated BCL2 expression. These data led us to speculate that inhibition of BCL2 in dasatinib-resistant LSC may sensitize LSC to TKI therapy. Treatment with a high-potency, novel pan-BCL2 family inhibitor, sabutoclax, in vitro led to a dose-dependent increase in apoptosis along with a decrease in the frequency of leukemic progenitors compared to vehicle treated controls. Normal human cord blood progenitor cells were less sensitive to sabutoclax treatment with IC50 approximately five times higher than that for blast crisis CML cells (210 nM versus 43 nM). Moreover, sabutoclax treatment did not inhibit cord blood colony formation or colony replating in vitro. Treatment of CML LSC-transplanted mice with sabutoclax led to a significant reduction in LSC burden in all hematopoietic organs analyzed. Sabutoclax treatment in vivo also sensitized surviving bone marrow blast crisis LSC to dasatinib treatment ex vivo. Importantly, there was no reduction in normal progenitor engraftment in bone marrow following sabutoclax treatment. These results demonstrate that marrow niche blast crisis CML LSC survival is driven by overexpression of multiple pro-survival BCL2 family isoforms rendering them susceptible to a novel pan, BCL2 antagonist, sabutoclax, at doses that spare normal hematopoietic progenitors. While BCL2 splice isform switching promotes LSC survival and TKI resistance, pan-BCL2 family member inhibition with sabutoclax eliminates LSC and may form the cornerstone of a clinical strategy to avert cancer progression and relapse. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Induction of BCL2 family member MCL1 as an early response to DNA damage

Oncogene ◽  
1997 ◽  
Vol 14 (9) ◽  
pp. 1031-1039 ◽  
Author(s):  
Qimin Zhan ◽  
Christine K Bieszczad ◽  
Insoo Bae ◽  
Albert J Fornace Jr ◽  
Ruth W Craig
Keyword(s):  
Dna Damage ◽  
Family Member ◽  
Early Response ◽  
Bcl2 Family ◽  
Bcl2 Family Member

scholarly journals MEK inhibition causes Bim stabilization and sensitivity to Bcl2 family member inhibitors in RAS-MAPK mutated neuroblastoma

2020 ◽  
Author(s):  
Thomas F Eleveld ◽  
Lindy Vernooij ◽  
Linda Schild ◽  
Bianca Koopmans ◽  
Lindy K Alles ◽  
...  
Keyword(s):  
Family Member ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Neuroblastoma Cells ◽  
Mek Inhibition ◽  
Bcl2 Family ◽  
Increased Sensitivity ◽  
Bcl2 Family Member

AbstractMutations affecting the RAS-MAPK pathway occur frequently in relapsed neuroblastoma tumors and are associated with response to MEK inhibition in vitro. However, these inhibitors alone do not lead to tumor regression in vivo, indicating the need for combination therapy. Through high throughput combination screening we identify Trametinib and inhibitors of the BCL2 family (Navitoclax and Venetoclax) as a promising combination in neuroblastoma cells with RAS-MAPK mutations. In these lines, inhibiting the RAS-MAPK pathway leads to Bim stabilization and increased sensitivity to compounds inhibiting Bim binding to Bcl2 family members. Combining Trametinib with BCL2 inhibitors causes increased growth inhibition compared to Trametinib only in NRAS mutant SKNAS xenografts, while BCL2 inihibitors alone do not affect growth of these tumors. These results show that MEK inhibitors and specific Bcl2 family member inhibitors are a potent combination for RAS-MAPK mutated neuroblastoma tumors.

scholarly journals Drug-resistance in doxorubicin-resistant FL5.12 hematopoietic cells: elevated MDR1, drug efflux and side-population positive and decreased BCL2-family member expression

Oncotarget ◽  
2017 ◽  
Vol 8 (68) ◽  
pp. 113013-113033 ◽  
Author(s):  
Linda S. Steelman ◽  
Steve L. Abrams ◽  
Peter Ruvolo ◽  
Vivian Ruvolo ◽  
Lucio Cocco ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Family Member ◽  
Side Population ◽  
Hematopoietic Cells ◽  
Drug Efflux ◽  
Bcl2 Family ◽  
Bcl2 Family Member
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