DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses

Bruneau, Sarah; Nakayama, Haruhiko; Woda, Craig B.; Flynn, Evelyn; Briscoe, David M.

doi:10.1182/blood-2013-03-488486

Cited by 38 publications

(51 citation statements)

References 49 publications

(59 reference statements)

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“…Our study also revealed that expression of P-S6 (S235/236) was significantly higher in CRC tissue than in normal colorectal mucosa (p<0.01). When greatly overexpressed, DEPTOR inhibits mTORC1 (Peterson et al, 2009;Bruneau et al, 2013;Meng et al, 2013;Zhang et al, 2013). In this study, DEPTOR was equally expressed in CRC and adjacent DOI:http://dx.doi.org/10.7314/APJCP.2014.15.11.4589 DEPTOR Expression Negatively Correlates with mTORC1 Activity and Tumor Progression in Colorectal Cancer normal colorectal mucosa.…”

Section: Discussionmentioning

confidence: 83%

DEPTOR Expression Negatively Correlates with mTORC1 Activity and Tumor Progression in Colorectal Cancer

Lai

Chen²,

Zhou³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The mammalian target of rapamycin (mTOR) signaling pathway is upregulated in the pathogenesis of many cancers, including colorectal cancer (CRC). DEPTOR is an mTOR inhibitor whose expression is negatively regulated by mTOR. However, the role of DEPTOR in the development of CRC is not known. The aim of this study was to investigate the expression of DEPTOR and mTORC1 activity (P-S6) in a subset of CRC patients and determine their relation to tumor differentiation, invasion, nodal metastasis and disease-free survival. Here, Immunohistochemical expression of P-S6 (S235/236) and DEPTOR were evaluated in 1.5 mm tumor cores from 90 CRC patients and in 90 samples of adjacent normal mucosa by tissue microarray. The expression of P-S6 (S235/236) was upregulated in CRC, with the positive rate of P-S6 (S235/236) in CRC (63.3%) significantly higher than that in control tissues (36.7%, 30%) (p<0.05). P-S6 (S235/236) also correlated with high tumor histologic grade (p=0.002), and positive nodal metastasis (p=0.002). In contrast, the expression level of DEPTOR was correlated with low tumor histological grade (p=0.006), and negative nodal metastasis (p=0.001). Interestingly, P-S6 (S235/236) expression showed a significant negative association with the expression of DEPTOR in CRC (p=0.011, R= -0.279). However, upregulation of P-S6 (S235/236) (p=0.693) and downregulation of DEPTOR (p=0.331) in CRC were not significantly associated with overall survival. Thus, we conclude that expression of DEPTOR negatively correlates with mTORC1 activity and tumor progression in CRC. DEPTOR is a potential marker for prognostic evaluation and a target for the treatment of CRC.

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Section: Discussionmentioning

confidence: 83%

DEPTOR Expression Negatively Correlates with mTORC1 Activity and Tumor Progression in Colorectal Cancer

Lai

Chen²,

Zhou³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…The main reason is that mTORC1 may have a more important role in angiogenesis than mTORC2 according to the previous studies. In addition, a recent study found that knockout of DEPTOR did not significantly affect the activity of Akt [18]. This means that loss of DEPTOR has no obvious effect on the mTORC2 pathway.…”

Section: Discussionmentioning

confidence: 93%

“…One study reported that DEPTOR regulates vascular EC activation and contributes to proinflammatory and angiogenic responses in vitro [18]. Our study examined the role of DEPTOR during angiogenesis in vivo and elucidated the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…One such regulatory protein is DEPTOR, which is an mTOR binding protein and functions to inhibit the mTORC1 and mTORC2 pathways [17]. It has been reported that DEPTOR regulates vascular EC activation and plays an important role in pro-inflammatory and angiogenic response in vitro [18]. However, the role of DEPTOR in angiogenesis in vivo remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Previous studies suggested an interaction between the mTOR-dependent metabolic state and the inflammatory properties of endothelial cells. 13 We now found a significant induction of endothelial autophagy after overexpression of miR-100 ( Figure 3A-3C), whereas inhibition of this microRNA led to a significant reduction of LC3B-positive Figure 2. Regulation of endothelial adhesion molecule expression is mammalian target of rapamycin complex 1 (mTORC1) dependent.…”

Section: Stimulation Of Endothelial Autophagy After Overexpression Ofmentioning

confidence: 99%

MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy

Pankratz

Hohnloser

Bemtgen

et al. 2018

Circulation Research

100

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Many attempts to modulate leukocyte-endothelial interaction to prevent or reduce excessive inflammatory reactions were made in the past. However, the basic regulatory principles of the endothelial inflammatory process remain unclear. It seems that the inhibition of individual components of the inflammatory cascade, for example, by a single antibody against an adhesion molecule, may not be enough to achieve a sustained effect on vascular inflammation.In the past years, microRNAs have been identified as important regulators of gene expression in a wide range of Molecular Medicine© 2017 American Heart Association, Inc. Rationale:The interaction of circulating cells within the vascular wall is a critical event in chronic inflammatory processes, such as atherosclerosis, but the control of the vascular inflammatory state is still largely unclear.Objective: This study was undertaken to characterize the function of the endothelial-enriched microRNA miR-100 during vascular inflammation and atherogenesis. Methods and Results:Based on a transcriptome analysis of endothelial cells after miR-100 overexpression, we identified miR-100 as a potent suppressor of endothelial adhesion molecule expression, resulting in attenuated leukocyte-endothelial interaction in vitro and in vivo as shown by flow cytometry and intravital imaging. Mechanistically, miR-100 directly repressed several components of mammalian target of rapamycin complex 1-signaling, including mammalian target of rapamycin and raptor, which resulted in a stimulation of endothelial autophagy and attenuated nuclear factor κB signaling in vitro and in vivo. In a low-density lipoprotein receptordeficient atherosclerotic mouse model, pharmacological inhibition of miR-100 resulted in enhanced plaque lesion formation and a higher macrophage content of the plaque, whereas a systemic miR-100 replacement therapy had protective effects and attenuated atherogenesis, resulting in a decrease of plaque area by 45%. Finally, analysis of miR-100 expression in >70 samples obtained during carotid endarterectomy revealed that local miR-100 expression was inversely correlated with inflammatory cell content in patients. Conclusions: In summary, we describe an anti-inflammatory function of miR-100 in the vascular response to injury and inflammation and identify an important novel modulator of mammalian target of rapamycin signaling and autophagy

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DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses

Cited by 38 publications

References 49 publications

DEPTOR Expression Negatively Correlates with mTORC1 Activity and Tumor Progression in Colorectal Cancer

DEPTOR Expression Negatively Correlates with mTORC1 Activity and Tumor Progression in Colorectal Cancer

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

MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy

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