Caspase-3, myogenic transcription factors and cell cycle inhibitors are regulated by leukemia inhibitory factor to mediate inhibition of myogenic differentiation

ABSTRACT We recently showed that a leukemia inhibitory factor (LIF)-engaged signaling pathway consisting of JAK1, STAT1, and STAT3 plays dual roles in myogenic differentiation: while it participates in myoblast proliferation, it also actively represses differentiation. Downregulation of this pathway is required at the onset of differentiation. However, it remained unclear how this is achieved mechanistically. We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. We further demonstrated that the SUMO E3-ligase activity of PIAS1 is dispensable for its role in myogenic differentiation. Collectively, our current study revealed a molecular mechanism that explains how the LIF-induced JAK1/STAT1/STAT3 pathway is downregulated upon myogenic differentiation.

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Developmental cooperation of leukemia inhibitory factor and insulin-like growth factor I in mice is tissue-specific and essential for lung maturation involving the transcription factors Sp3 and TTF-1

Mechanisms of Development ◽

10.1016/s0925-4773(02)00449-5 ◽

2003 ◽

Vol 120 (3) ◽

pp. 349-361 ◽

Cited By ~ 23

Author(s):

Jose G. Pichel ◽

Carmen Fernández-Moreno ◽

Carlos Vicario-Abejón ◽

Pilar S. Testillano ◽

Paul H. Patterson ◽

...

Keyword(s):

Transcription Factors ◽

Growth Factor ◽

Leukemia Inhibitory Factor ◽

Inhibitory Factor ◽

Insulin Like Growth Factor ◽

Lung Maturation ◽

Tissue Specific ◽

Factor I ◽

Growth Factor I

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Selective Requirement for Polycomb Repressor Complex 2 in the Generation of Specific Hypothalamic Neuronal Sub-types

10.1101/2021.07.28.454060 ◽

2021 ◽

Author(s):

Stefan S Thor ◽

Behzad Yaghmaeian Salmani ◽

Brad Balderson ◽

Susanne Bauer ◽

Helen Ekman ◽

...

Keyword(s):

Cell Cycle ◽

Transcription Factors ◽

Ectopic Expression ◽

Signalling Pathways ◽

Homeotic Genes ◽

Loss Reduction ◽

Double Positive ◽

Repressor Complex ◽

Gene Regulatory ◽

Cell Cycle Inhibitors

The hypothalamus displays staggering cellular diversity, chiefly established during embryogenesis by the interplay of several signalling pathways and a battery of transcription factors. However, the contribution of epigenetic cues to hypothalamus development remains unclear. We mutated the Polycomb Repressor Complex 2 gene Eed in the developing mouse hypothalamus, which resulted in the loss of H3K27me3; a fundamental epigenetic repressor mark. This triggered ectopic expression of posteriorly expressed regulators (e.g., Hox homeotic genes), upregulation of cell cycle inhibitors and reduced proliferation. Surprisingly, despite these effects, single cell transcriptomic analysis revealed that the majority of neuronal subtypes were still generated in Eed mutants. However, we observed an increase in Glutamatergic/GABAergic double-positive cells, as well as loss/reduction of dopamine, Hypocretin/Orexin and Tac2 neurons. These findings indicate that many aspects of the hypothalamic gene regulatory flow can proceed without the key H3K27me3 epigenetic repressor mark, and points to a unique sensitivity of particular neuronal sub-types to a disrupted epigenomic landscape.

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Cell cycle synchronization of leukemia inhibitory factor (LIF)-dependent porcine-induced pluripotent stem cells and the generation of cloned embryos

Cell Cycle ◽

10.4161/cc.28176 ◽

2014 ◽

Vol 13 (8) ◽

pp. 1265-1276 ◽

Cited By ~ 13

Author(s):

Ye Yuan ◽

Kiho Lee ◽

Kwang-Wook Park ◽

Lee Spate ◽

Randall S. Prather ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Leukemia Inhibitory Factor ◽

Inhibitory Factor ◽

Cell Cycle Synchronization ◽

Induced Pluripotent

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Oxidative Stress Activates the Transcription Factors FoxO 1a and FoxO 3a in the Hippocampus of Rats Exposed to Low Doses of Ozone

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/805764 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

Nancy P. Gómez-Crisóstomo ◽

Erika Rodríguez Martínez ◽

Selva Rivas-Arancibia

Keyword(s):

Oxidative Stress ◽

Cell Cycle ◽

Transcription Factors ◽

Caspase 3 ◽

Low Doses ◽

Cyclin D2 ◽

Regulatory Pathways ◽

Forkhead Box ◽

Male Wistar Rats ◽

Active Caspase

The exposure to low doses of ozone induces an oxidative stress state, which is involved in neurodegenerative diseases. Forkhead box O (FoxO) family of transcription factors are activated by oxidative signals and regulate cell proliferation and resistance to oxidative stress. Our aim was to study the effect of chronic exposure to ozone on the activation of FoxO 1a and FoxO 3a in the hippocampus of rats. Male Wistar rats were divided into six groups and exposed to 0.25 ppm of ozone for 0, 7, 15, 30, 60, and 90 days. After treatment, the groups were processed for western blotting and immunohistochemistry against FoxO 3a, Mn SOD, cyclin D2, FoxO 1a, and active caspase 3. We found that exposure to ozone increased the activation of FoxO 3a at 30 and 60 days and expression of Mn SOD at all treatment times. Additionally, increases in cyclin D2 from 7 to 90 days; FoxO 1a at 15, 30, and 60 days; and activate caspase 3 from 30 to 60 days of exposure were noted. The results indicate that ozone alters regulatory pathways related to both the antioxidant system and the cell cycle, inducing neuronal reentry into the cell cycle and apoptotic death.

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Cell-Specific Pituitary Gene Expression Profiles after Treatment with Leukemia Inhibitory Factor Reveal Novel Modulators for Proopiomelanocortin Expression

Endocrinology ◽

10.1210/en.2003-0897 ◽

2004 ◽

Vol 145 (2) ◽

pp. 867-880 ◽

Cited By ~ 22

Author(s):

Rula A. Abbud ◽

Robert Kelleher ◽

Shlomo Melmed

Keyword(s):

Transcription Factors ◽

Leukemia Inhibitory Factor ◽

Expression Profiles ◽

Tyrosine Phosphatase ◽

Sh2 Domain ◽

Inhibitory Factor ◽

Cytokine Signaling ◽

Signal Transducer ◽

Induced Expression ◽

Transcription 3

Abstract Leukemia inhibitory factor (LIF) mediates the hypothalamo-pituitary-adrenal stress response. Transgenic mice overexpressing LIF in the developing pituitary have altered pituitary differentiation with expansion of corticotropes, maintenance of Rathke’s cleft cysts, and suppression of all other pituitary cell types. Affymetrix GeneChips were used to identify modulators of LIF effects in corticotrope (AtT-20) and somatolactotrope (GH3) cells. In addition to genes known to respond to LIF in corticotrope cells [e.g. suppressor of cytokine signaling-3 (SOCS-3), signal transducer and activator of transcription-3, SH2 domain-containing tyrosine phosphatase-1, and proopiomelanocortin (POMC)], corticotrope-specific changes were also observed for genes involved in glycolysis and gluconeogenesis, transcription factors, signaling molecules, and expressed sequence tags. Two transcription factors identified, CCAAT/enhancer-binding protein β (C/EBPβ) and glial cell-derived neurotrophic factor (GDNF)-inducible factor (GIF), dose-dependently induced expression of the rat POMC promoter when overexpressed in AtT-20 cells. LIF further induced POMC transcription with C/EBPβ, but not with GIF. C/EBPβ also induced expression of the SOCS-3 promoter that was further enhanced by cotreatment with LIF. However, GIF did not affect SOCS-3 expression. These results indicate that C/EBPβ and GIF are downstream effectors of LIF corticotrope action. LIF also stimulates the expression of inhibitors of its actions, such as SOCS-3 and SH2 domain-containing tyrosine phosphatase-1. α2-HS-glycoprotein (AHSG)/fetuin, a secreted protein that antagonizes bone TGFβ/bone morphogenic protein signaling, was induced by LIF in a signal transducer and activator of transcription-3-dependent fashion. Pretreatment with AHSG/fetuin blocked LIF-induced expression of the POMC promoter independently of SOCS-3. Thus, using GeneChips, C/EBPβ and GIF have been identified as novel mediators and AHSG/fetuin as an inhibitor of LIF action in corticotropes.

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