Survival control of malignant lymphocytes by anti-apoptotic MCL-1

Fernández-Marrero, Yuniel; S, Spinner; Kaufmann, Thomas; Jost, Philipp J.

doi:10.1038/leu.2016.213

Cited by 38 publications

(46 citation statements)

References 100 publications

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“…In chronic infection, Mcl-1 is downregulated in CD127 low antigen specific CTLs along with up-regulation of Bim and this causes apoptosis of CD8 + T cells (272) or hyporeactivity of CTLs, which could possibly be treated by apoptosis inhibition or IL-7 treatment (273). Conversely, Mcl-1 enhances survival in a variety of cancers including T cell lymphomas and various Mcl-1 inhibitors are being explored (274). Given the robust loss of cells anytime Mcl-1 is deleted, there are some substantial concerns about the potential cytotoxicity of Mcl-1 inhibitors.…”

Section: Bcl-2 Family Membersmentioning

confidence: 99%

Dying to protect: cell death and the control of T‐cell homeostasis

Shanmuganad

Carroll

et al. 2017

Immunological Reviews

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Summary T cells play a critical role in immune responses as they specifically recognize peptide/MHC complexes with their T cell receptors (TCRs) and initiate adaptive immune responses. While T cells are critical for performing appropriate effector functions and maintaining immune memory, they also can cause autoimmunity or neoplasia if misdirected or dysregulated. Thus, T cells must be tightly regulated from their development onward. Maintenance of appropriate T cell homeostasis is essential to promote protective immunity and limit autoimmunity and neoplasia. This review will focus on the role of cell death in maintenance of T cell homeostasis and outline novel therapeutic strategies tailored to manipulate cell death to limit T cell survival (eg autoimmunity and transplantation) or enhance T cell survival (eg vaccination, immune-deficiency).

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Section: Bcl-2 Family Membersmentioning

confidence: 99%

Dying to protect: cell death and the control of T‐cell homeostasis

Shanmuganad

Carroll

et al. 2017

Immunological Reviews

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“…Mcl-1 degradation is regulated by its phosphorylation at several sites, leading to subsequent ubiquitination by E3 ligases such as F-box and WD repeat domain-containing 7 (FBW7), Mule, and β-TrCP (6–9). Mcl-1 depletion clearly contributes to apoptosis in hematopoietic cells (10,11). However, the role of Mcl-1 degradation in solid tumor cells is unclear, as Mcl-1 depletion typically occurs prior to the onset of apoptosis in response to therapeutic treatment, and by itself, is insufficient to trigger cell death (12).…”

Section: Introductionmentioning

confidence: 99%

Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells

et al. 2017

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The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells. In this setting, Mcl-1 degradation was induced by a variety of multi-kinase inhibitor drugs, where it relied upon GSK3β phosphorylation and FBW7-dependent ubiquitination. Specific blockade by genetic knock-in (KI) abolished apoptotic responses and conferred resistance to kinase inhibitors. Mcl-1-KI also suppressed the anti-angiogenic and anti-hypoxic effects of kinase inhibitors in the tumor microenvironment. Interestingly, these same inhibitors also induced the BH3-only Bcl-2 family protein PUMA, which is required for apoptosis. Degradation-resistant Mcl-1 bound and sequestered PUMA from other pro-survival proteins to maintain cell survival, which was abolished by small-molecule Mcl-1 inhibitors. Our findings establish a pivotal role for Mcl-1 degradation in the response of colon cancer cells to targeted therapeutics, and they provide a useful rational platform to develop Mcl-1-targeting agents that can overcome drug resistance.

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“…3b). Given that GSK-3 is known to regulate stability of the Bcl-2 family survival protein Mcl-1 [31][32][33][34] we performed immunoblot analysis on sorted DP thymocytes for Mcl-1 protein levels. LckCre + GSK-3αβ fl/fl DP thymocytes exhibited significantly higher levels of Mcl-1, consistent with enhanced DP cell survival ( Fig.…”

Section: Lckcrementioning

confidence: 99%

“…While it has been reported that constitutive activation of Akt in absence of pre-TCR and NOTCH signals can prevent programmed cell death of DN thymocytes independent of several Bcl-2 members there is evidence that Bcl-2 family members such as Mcl-1 play a crucial role in T cell survival, development and tumorigenesis [30][31][32][33][34][35] . GSK-3 regulates Mcl-1 stability through ubiquitin-mediated degradation 34,35 .…”

Section: Introductionmentioning

confidence: 99%

Regulation of thymocyte β-selection, development and positive selection by glycogen synthase kinase-3

Parsons

Patel

Doble

et al. 2019

Preprint

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Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase, that exists as two isoforms in mammals, GSK-3α and GSK-3β, that are key downstream mediators of the phosphatidylinositol 3' kinase, Wnt, Notch and other pathways. Here, we report that simultaneous inactivation of both GSK-3α and GSK-3β during early thymocyte ontogeny has profound effects on both β-selection and positive selection, key checkpoints essential to producing functionally mature αβ T cells. Conditional GSK-3α/β knockout animals (LckCre + GSK-3αβ fl/fl ) possessed pre-double positive (pre-DP) thymocytes (CD4 -CD8 -CD117 -CD25 -) with compromised TCRβ chain expression along with elevated levels of β-catenin and reduced Notch activity. β-selection was impaired allowing pre-DP thymocytes to differentiate to DP thymocytes (CD4 + CD8 + ) while bypassing strict requirements for productive TCRβ chain rearrangements and functional expression. Also impaired was the requisite pre-TCR and Notch-mediated expansion that normally precedes differentiation to the DP stage. Consequently, LckCre + GSK-3αβ fl/fl mice initially generated fewer DP thymocytes that expressed significantly reduced levels of mature TCR. The aberrant DP thymocytes expressed high levels of the pro-survival Bcl-2 family member Mcl-1, failed positive selection and accumulated as CD4 hi CD8 lo positive selection intermediates resulting in loss of both mature CD4 and CD8 lineages.LckCre + GSK-3αβ fl/fl mice succumbed to oligoclonal peripheral lymphomas with high penetrance. These data reveal essential roles for GSK-3 in several checkpoints of early T cell development.GSK-3αβ fl/fl CD3 + CD24 -CD8 SP's. Fig. 4. A. Intracellular β-catenin expression expressed as median fluorescent intensity within gated thymocyte sub-populations. B. Splenic CD4 + and CD8 + SP populations from LckCre + GSK-3αβ fl/fl mice had comparable levels of TCR and CD3 expression to LckCre -GSK-3αβ fl/fl mice even though numbers were significantly reduced. C. FACS of 5 individual LckCre + GSK-3αβ fl/fl lymphomas reveal heterogeneity as judged by CD3, CD4, CD8, and CD19 markers. Suppl.

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Survival control of malignant lymphocytes by anti-apoptotic MCL-1

Cited by 38 publications

References 100 publications

Dying to protect: cell death and the control of T‐cell homeostasis

Dying to protect: cell death and the control of T‐cell homeostasis

Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells

Regulation of thymocyte β-selection, development and positive selection by glycogen synthase kinase-3

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