Requirement of GSK-3 for PUMA induction upon loss of pro-survival PI3K signaling

Schubert, Florian; Rapp, J.; Brauns-Schubert, Prisca; Schlicher, Lisa; Stock, Kerstin; Wissler, Manuela; Weiß, Martina; Charvet, Céline; Borner, Christoph; Maurer, Ulrich

doi:10.1038/s41419-018-0502-4

Cited by 9 publications

(8 citation statements)

References 26 publications

(38 reference statements)

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“…[19][20][21] GSK3 is a major AKT target involved in the regulation of cell death by controlling BCL2family proteins. 8,[22][23][24][25] Here, we show that FOXO1/3 and GSK3 are AKT-restrained tumor suppressors and that the expression of FOXO-repressed genes, indicative of increased AKT activity, has prognostic value in a cohort of patients with MM. Mechanistically, we provide evidence that FOXO and GSK3 provoke cell death in a nonredundant fashion through negative regulation of MCL1, a major antiapoptotic protein in plasma cells and MM.…”

Section: Introductionmentioning

confidence: 68%

AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma

Bloedjes¹,

Wilde²,

Maas³

et al. 2020

Blood Advances

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The phosphatidylinositide-3 kinases and the downstream mediator AKT drive survival and proliferation of multiple myeloma (MM) cells. AKT signaling is active in MM and has pleiotropic effects; however, the key molecular aspects of AKT dependency in MM are not fully clear. Among the various downstream AKT targets are the Forkhead box O (FOXO) transcription factors (TFs) and glycogen synthase kinase 3 (GSK3), which are negatively regulated by AKT signaling. Here we show that abrogation of AKT signaling in MM cells provokes cell death and cell cycle arrest, which crucially depends on both FOXO TFs and GSK3. Based on gene expression profiling, we defined a FOXO-repressed gene set that has prognostic significance in a large cohort of patients with MM, indicating that AKT-mediated gene activation is associated with inferior overall survival. We further show that AKT signaling stabilizes the antiapoptotic myeloid cell leukemia 1 (MCL1) protein by inhibiting FOXO- and GSK3-mediated MCL1 turnover. In concordance, abrogation of AKT signaling greatly sensitized MM cells for an MCL1-targeting BH3-mimetic, which is currently in clinical development. Taken together, our results indicate that AKT activity is required to restrain the tumor-suppressive functions of FOXO and GSK3, thereby stabilizing the antiapoptotic protein MCL1 in MM. These novel insights into the role of AKT in MM pathogenesis and MCL1 regulation provide opportunities to improve targeted therapy for patients with MM.

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Section: Introductionmentioning

confidence: 68%

AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma

Bloedjes¹,

Wilde²,

Maas³

et al. 2020

Blood Advances

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“…Puma is reported to be involved in p53-dependent or independent cell apoptosis and tumor processing (40)(41)(42). Puma is significantly upregulated when apoptosis occurs (43). Caspase is the operator of apoptosis, which is responsible for the transfer, transduction and integration of apoptotic signals (44).…”

Section: Discussionmentioning

confidence: 99%

The X box binding protein 1/C/EBP homologous protein pathway induces apoptosis of endothelial cells under hyperglycemia

Tang

Zheng

et al. 2022

Exp Ther Med

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Venous endothelial cell apoptosis can be induced by endoplasmic reticulum (ER) stress, thus serving an important role in the formation of deep venous thrombosis. X-box binding protein 1 (XBP1) is a protein associated with ER. The present study aimed to explore the function of XBP1/C/EBP homologous protein (CHOP) pathway in the process of endothelial cell apoptosis under hyperglycemia. Small interfering (si)RNAs targeting XBP1 and CHOP were designed to downregulate the expression of XBP1 and CHOP in human umbilical vein endothelial cell, respectively. Flow cytometry was used to determine cell apoptosis. The expression of XBP1, glucose-regulated protein 78 (GRP78), CHOP, Puma, cleaved caspase-3 and Cytochrome c was evaluated by western blotting. There were seven groups of cells that were used in the present study: i) Control (5.5 mM D-glucose); ii) hypertonic (hypertonic control, 27.8 mM mannitol and 5.5 mM D-glucose); iii) 16.7 mM D-glucose; iv) 33.3 mM D-glucose; v) 33.3 mM + NC (33.3 mM D-glucose incubated with NC); vi) 33.3 mM + si-XBP1 (33.3 mM D-glucose incubated with siRNA against XBP1); and vii) 33.3 mM + si-CHOP (33.3 mM D-glucose incubated with siRNA against CHOP). Compared with the control, the apoptosis rate of human umbilical vein endothelial cells (HUVECs) increased greatly with the increase in the concentration of D-glucose. Compared with the 33.3 mM D-glucose group, the HUVECs incubated with 33.3 mM D-glucose and si-XBP1 or 33.3 mM D-glucose and si-CHOP demonstrated a significantly lower apoptosis rate. Compared with the control, XBP1, GRP78, CHOP, Puma, cleaved caspase-3 and cytochrome c were significantly upregulated in the hypertonic, 16.7 mM D-glucose, 33.3 mM D-glucose and 33.3 mM + negative control (NC) groups. Compared with the 33.3 mM D-glucose group, the expression levels of XBP1, GRP78, CHOP, Puma, cleaved caspase-3 and cytochrome c in the 33.3 mM + si-XBP1 or 33.3 mM + si-CHOP groups significantly decreased. High dosage of glucose induced endothelial cell apoptosis by promoting the expression of apoptotic proteins by activating endoplasmic reticulum stress. XBP1/CHOP may be a potential target for the treatment of deep vein thrombosis as one of the key pathways regulating ERS by regulating apoptosis of endothelial cells.

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“…In addition, autophagy inhibition increases the levels of FOXO3a transcription factor, and promotes PUMA upregulation, thereby increasing apoptosis [ 55 ]. Glycogen synthase kinase-3β (GSK-3β) also regulates PUMA expression, and GSK-3 suppression prevents PUMA induction by FOXO3a and P53 on growth factor withdrawal [ 56 ].…”

Section: Puma-mediated Signaling Pathwaysmentioning

confidence: 99%

“…GSK3 regulates ER-stress-induced CHOP expression in neuronal cells [ 98 ]. GSK-3β also regulates PUMA expression [ 56 ]. TRIB3/TRB3 (a target of CHOP) is induced later than CHOP during ER stress [ 98 ], and it can promote PUMA expression in a FOXO3a-dependent manner through the dephosphorylation of AKT in PC-12 cells [ 98 ].…”

Section: Puma Deficiency Significantly Protects Neurons From Er-stress-induced Apoptosis For Neurodegenerative Diseasesmentioning

confidence: 99%

The role of P53 up-regulated modulator of apoptosis (PUMA) in ovarian development, cardiovascular and neurodegenerative diseases

2021

Apoptosis

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P53 up-regulated modulator of apoptosis (PUMA), a pro-apoptotic BCL-2 homology 3 (BH3)-only member of the BCL-2 family, is a direct transcriptional target of P53 that elicits mitochondrial apoptosis under treatment with radiation and chemotherapy. It also induces excessive apoptosis in cardiovascular and/or neurodegenerative diseases. PUMA has been found to play a critical role in ovarian apoptosis. In the present paper, we review the progress of the study in PUMA over the past two decades in terms of its inducement and/or amplification of programmed cell death and describe recent updates to the understanding of both P53-dependent and P53-independent PUMA-mediated apoptotic pathways that are implicated in physiology and pathology, including the development of the ovary and cardiovascular and neurodegenerative diseases. We propose that PUMA may be a key regulator during ovary development, provide a model for PUMA-mediated apoptotic pathways, including intrinsic and extrinsic apoptotic pathways.

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Requirement of GSK-3 for PUMA induction upon loss of pro-survival PI3K signaling

Cited by 9 publications

References 26 publications

AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma

AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma

The X box binding protein 1/C/EBP homologous protein pathway induces apoptosis of endothelial cells under hyperglycemia

The role of P53 up-regulated modulator of apoptosis (PUMA) in ovarian development, cardiovascular and neurodegenerative diseases

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