Control of Pim2 kinase stability and expression in transformed human haematopoietic cells

The constitutively-active kinase Pim2 overexpressed in transformed cells constitutes an attractive target in cancer. We show that both Pim2 degradation realized by the proteasome in an ubiquitin-independent manner and Pim2 translation are constitutive.

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Non-canonical glutamate-cysteine ligase activity protects against ferroptosis

10.1101/2020.05.29.123802 ◽

2020 ◽

Author(s):

Yun Pyo Kang ◽

Andrea Mockabee-Macias ◽

Chang Jiang ◽

Isaac S. Harris ◽

Gina M. DeNicola

Keyword(s):

Cell Death ◽

Redox Homeostasis ◽

Catalytic Subunit ◽

Transformed Cells ◽

Independent Manner ◽

Glutamate Cysteine Ligase ◽

Cellular Redox ◽

Glutathione Synthesis ◽

Dependent Form ◽

Glutamate Homeostasis

AbstractCysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are uncharacterized. Here, we find that cystine starvation promotes ferroptosis not only through the inhibition of glutathione (GSH) synthesis, but also through the accumulation of glutamate. Surprisingly, we find that glutamate-cysteine ligase catalytic subunit (GCLC) prevents glutamate accumulation through the generation of alternative γ-glutamyl peptides. Further, inhibition of GCLC accelerates ferroptosis under cystine starvation in a GSH-independent manner. These results indicate that GCLC has an additional, non-canonical role in the protection against ferroptosis to maintain glutamate homeostasis under cystine starvation.

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Retinal degeneration in mice expressing the constitutively active G90D rhodopsin mutant

Human Molecular Genetics ◽

10.1093/hmg/ddaa008 ◽

2020 ◽

Vol 29 (6) ◽

pp. 881-891 ◽

Cited By ~ 1

Author(s):

Alejandro T Colozo ◽

Sreelakshmi Vasudevan ◽

Paul S-H Park

Keyword(s):

Retinal Degeneration ◽

Night Blindness ◽

Photoreceptor Cells ◽

Active Species ◽

Rod Photoreceptor ◽

Constitutive Activity ◽

Congenital Stationary Night Blindness ◽

Independent Manner ◽

Multiple Species ◽

Constitutively Active

Abstract Rhodopsin is the G protein-coupled receptor in rod photoreceptor cells that initiates vision upon photon capture. The light receptor is normally locked in an inactive state in the dark by the covalently bound inverse agonist 11-cis retinal. Mutations can render the receptor active even in the absence of light. This constitutive activity can desensitize rod photoreceptor cells and lead to night blindness. A G90D mutation in rhodopsin causes the receptor to be constitutively active and leads to congenital stationary night blindness, which is generally thought to be devoid of retinal degeneration. The constitutively active species responsible for the night blindness phenotype is unclear. Moreover, the classification as a stationary disease devoid of retinal degeneration is also misleading. A transgenic mouse model for congenital stationary night blindness that expresses the G90D rhodopsin mutant was examined to better understand the origin of constitutive activity and the potential for retinal degeneration. Heterozygous mice for the G90D mutation did not exhibit retinal degeneration whereas homozygous mice exhibited progressive retinal degeneration. Only a modest reversal of retinal degeneration was observed when transducin signaling was eliminated genetically, indicating that some of the retinal degeneration occurred in a transducin-independent manner. Biochemical studies on purified rhodopsin from mice indicated that multiple species can potentially contribute to the constitutive activity causing night blindness.

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