p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation

González‐Terán, Bárbara; López, Juan Antonio; Rodrı́guez, Elena; Leiva, Luis; Martı́nez-Martı́nez, Sara; Bernal, Juan A.; Jiménez-Borreguero, Luis Jesús; Redondo, Juan Miguel; Vázquez, Jesús; Sabio, Guadalupe

doi:10.1038/ncomms10477

Cited by 75 publications

(76 citation statements)

References 49 publications

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“…DEPTOR is an mTORC1 inhibitor [30, 31], which is closely related to cell proliferation, inflammation, obesity, and cancer [32, 33] and directly connected with cardiovascular disease [34, 35]. One study reported that DEPTOR regulates vascular EC activation and contributes to proinflammatory and angiogenic responses in vitro [18].…”

Section: Discussionmentioning

confidence: 99%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

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Section: Discussionmentioning

confidence: 99%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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“…To test if p38 is required for the negative correlation of cell size with G1 length, we 87 examined a panel of specific inhibitors against MAPK pathways and tested whether any of these inhibitors break 88 the negative correlation induced by rapamycin. Significantly, inhibition of p38, but not the JNK or ERK 89 pathways, consistently breaks the negative correlation between size and proportion of cells in G1 (Figure 2 B-E, 90 isoforms with regard to size control (13,16). One difference between the chemical inhibition and the knockdown 96 experiments is a greater reduction in cell size observed following chemical inhibition of p38.…”

Section: Results 27mentioning

confidence: 81%

Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

Liu

Ginzberg

Patel

et al. 2017

Preprint

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1Animal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms 2 that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is 3 promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying 4 this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is 5 involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend 6 more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension 7 in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a 8 model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase 9 cell size uniformity. 10

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“…In this way, the β-TrCP increases mTOR activity resulting in an inhibition of autophagy (Figure 3A) 95,96 . Multiple studies have identified DEPTOR in cardiomyocytes, implicating p38 activity in its regulation 97 .…”

Section: Therapies Targeting Cardiac Autophagy To Promote Cardioprotementioning

confidence: 99%

Cardiac ubiquitin ligases: Their role in cardiac metabolism, autophagy, cardioprotection and therapeutic potential

Parry¹,

Willis²

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Both the ubiquitin-proteasome system (UPS) and the lysosomal autophagy system have emerged as complementary key players responsible for the turnover of cellular proteins. The regulation of protein turnover is critical to cardiomyocytes as post-mitotic cells with very limited regenerative capacity. In this focused review, we describe the emerging interface between the UPS and autophagy, with E3’s regulating autophagy at two critical points through multiple mechanisms. Moreover, we discuss recent insights in how both the UPS and autophagy can alter metabolism at various levels, to present new ways to think about therapeutically regulating autophagy in a focused manner to optimize disease-specific cardioprotection, without harming the overall homeostasis of protein quality control.

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p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation

Cited by 75 publications

References 49 publications

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

Cardiac ubiquitin ligases: Their role in cardiac metabolism, autophagy, cardioprotection and therapeutic potential

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