Translation control can shape TP53-dependent cell fate

Abstract Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-κB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-κB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2–driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C se-lectively blocks induction of NF-κB–dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C–dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes.

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Jagged1 is the major regulator of notch-dependent cell fate in proximal airways

Developmental Dynamics ◽

10.1002/dvdy.23965 ◽

2013 ◽

Vol 242 (6) ◽

pp. 678-686 ◽

Cited By ~ 37

Author(s):

Shubing Zhang ◽

Amanda J. Loch ◽

Freddy Radtke ◽

Sean E. Egan ◽

Keli Xu

Keyword(s):

Cell Fate ◽

Dependent Cell

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Decoding Activation of ILC2 using Time-Dependent Cell-State Selection

10.21203/rs.3.rs-345276/v1 ◽

2021 ◽

Author(s):

Yumiko Tanaka ◽

Mai Yamagishi ◽

Yasutaka Motomura ◽

Takashi Kamatani ◽

Yusuke Oguchi ◽

...

Keyword(s):

Cell Fate ◽

Lymphoid Cells ◽

Time Dependent ◽

Molecular Networks ◽

Regulatory Function ◽

Fate Determination ◽

Cell State ◽

Fundamental Process ◽

Dependent Cell ◽

State Selection

Abstract Cell fate determination, a fundamental process of life, is controlled through dynamic intracellular molecular networks. However, the low population of cells at the switching period of fate determination has made it technically difficult to analyze the transcriptome of the stage. Here we developed the Time-Dependent Cell-State Selection (TDCSS) technique, which detects an index of the switching period by live-cell imaging of secretion activity followed by simultaneous recoveries of the indexed cells for subsequent transcriptome analysis. Specifically, we used the TDCSS technique to study the switching period of group2 innate lymphoid cells (ILC2s) activation indexed by interleukin (IL)-13 secretion onset. TDCSS newly classified time-dependent genes, including transiently induced genes (TIGs). The finding of IL4 and MIR155HG as TIGs demonstrated their regulatory function of ILC2s activation.

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Chemical Disruption of Wnt-dependent Cell Fate Decision-making Mechanisms in Cancer and Regenerative Medicine

Current Medicinal Chemistry ◽

10.2174/0929867322666150827094015 ◽

2015 ◽

Vol 22 (35) ◽

pp. 4091-4103 ◽

Cited By ~ 12

Author(s):

L. Lum ◽

C. Chen

Keyword(s):

Decision Making ◽

Regenerative Medicine ◽

Cell Fate ◽

Cell Fate Decision ◽

Dependent Cell ◽

Fate Decision

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FRS2α-dependent cell fate transition during endocardial cushion morphogenesis

Developmental Biology ◽

10.1016/j.ydbio.2019.10.022 ◽

2020 ◽

Vol 458 (1) ◽

pp. 88-97

Author(s):

Dongying Chen ◽

Xiaolong Zhu ◽

Natalie Kofler ◽

Yidong Wang ◽

Bin Zhou ◽

...

Keyword(s):

Cell Fate ◽

Endocardial Cushion ◽

Dependent Cell ◽

Endocardial Cushion Morphogenesis

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Arkadia via SNON enables NODAL-SMAD2/3 signaling effectors to transcribe different genes depending on their levels

10.1101/487371 ◽

2018 ◽

Cited By ~ 1

Author(s):

Jonathon M. Carthy ◽

Marilia Ioannou ◽

Vasso Episkopou

Keyword(s):

Cell Fate ◽

Target Genes ◽

Embryonic Stem ◽

Null Mouse ◽

Specific Cell ◽

Cell Fates ◽

Mammalian Embryo ◽

Cell Fate Decisions ◽

Dependent Cell ◽

Anterior Posterior

AbstractHow cells assess levels of signaling and select to transcribe different target genes depending on the levels of activated effectors remains elusive. High NODAL-signalling levels specify anterior/head, lower specify posterior, and complete loss abolishes anterior-posterior patterning in the mammalian embryo. Here we show that cells assess NODAL-activated SMAD2 and SMAD3 (SMAD2/3) effector-levels by complex formation and pairing each effector with the co-repressor SNON, which is present in the cell before signaling. These complexes enable the E3-ubiquitin ligase Arkadia (RNF111) to degrade SNON. High SMAD2/3 levels can saturate and remove SNON, leading to derepression and activation of a subset of targets (high targets) that are highly susceptible to SNON repression. However, low SMAD2/3 levels can only reduce SNON preventing derepression/activation of high targets. Arkadia degrades SNON transiently only upon signaling exposure, leading to dynamic signaling-responses, which most likely initiate level-specific cell-fate decisions. Arkadia-null mouse embryos and Embryonic Stem Cells (ESC) cannot develop anterior tissues and head. However, SnoN/Arkadia, double-null embryos and ESCs are rescued confirming that Arkadia removes SNON, to achieve level-dependent cell-fatesOne Sentence SummarySignaling intensity induces equivalent degradation of a transcriptional repressor leading to level-dependent responses.

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Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions

eLife ◽

10.7554/elife.35407 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 6

Author(s):

Achim Werner ◽

Regina Baur ◽

Nia Teerikorpi ◽

Deniz U Kaya ◽

Michael Rape

Keyword(s):

Neural Crest ◽

Cell Fate ◽

Posttranslational Modifications ◽

E3 Ligase ◽

Cell Fate Decisions ◽

Regulatory Circuit ◽

Dependent Cell ◽

Slow Rise ◽

Regulated Gene Expression ◽

Powerful Mechanism

Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8. We found that CUL3KBTBD8 monoubiquitylates its essential targets only after these have been phosphorylated in multiple motifs by CK2, a kinase whose levels gradually increase during embryogenesis. Its dependency on multisite phosphorylation allows CUL3KBTBD8 to convert the slow rise in embryonic CK2 into decisive recognition of ubiquitylation substrates, which in turn is essential for neural crest specification. We conclude that multisite dependency of an E3 ligase provides a powerful mechanism for switch-like cell fate transitions controlled by monoubiquitylation.

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