Last update 19 Sep 2024

TRAP1

Last update 19 Sep 2024

Basic Info

Synonyms

Heat shock protein 75 kDa, mitochondrial, HSP 75, HSP75

+ [7]

Introduction

Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, downstream of PINK1 and mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA.

Drugs associated with TRAP1

ACU-D3

Target

TRAP1

Mechanism

TRAP1 antagonists

Active Org.

Accuitis, Inc.

Originator Org.

Accuitis, Inc.

Active Indication

Melanoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SH-491

Target

CTSK x MMP9 x TRAP1

Mechanism

CTSK inhibitors [+2]

Active Org.

East China Normal University

Originator Org.

East China Normal University

Active Indication

Osteoporosis

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TRAP1

100 Translational Medicine associated with TRAP1

0 Patents (Medical) associated with TRAP1

1,102

Literatures (Medical) associated with TRAP1

08 Aug 2024·Nature

In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution

Article

Author: Khandekar, Ameya ; Kretz, Jonas A ; Ellis, Stephanie J ; Duré, Clara ; Lee, Minkyoung ; Baghai Sain, Simona ; Bernasconi, Martino ; Valdivia-Francia, Fabiola ; Hyams, Katie ; Pohly, Marcel ; Ghoshdastider, Umesh ; Ficht, Xenia ; Forny, Merima ; Renz, Peter F ; Ormiston, Mark ; Moor, Andreas E ; Sendoel, Ataman

AbstractThe tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1–3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial–mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.

01 Aug 2024·European Journal of Pharmacology

Porphyrin derivatives inhibit tumor necrosis factor α-induced gene expression and reduce the expression and increase the cross-linked forms of cellular components of the nuclear factor κB signaling pathway

Article

Author: Sasaki, Saki ; Kataoka, Takao ; Osada, Hiroyuki ; Morimoto, Kyoko ; Tamura, Ryuichi ; Baba, Kosuke ; Vu, Nhat Thi ; Vu, Quy Van ; Hirano, Hiroyuki

The transcription factor nuclear factor κB (NF-κB) is activated by proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and Toll-like receptor (TLR) ligands. Screening of NPDepo chemical libraries identified porphyrin derivatives as anti-inflammatory compounds that strongly inhibited the up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression induced by TNF-α, interleukin-1α, the TLR3 ligand, and TLR4 ligand in human umbilical vein endothelial cells. In the present study, the mechanisms of action of porphyrin derivatives were further elucidated using human lung adenocarcinoma A549 cells. Porphyrin derivatives, i.e., dimethyl-2,7,12,18-tetramethyl-3,8-di(1-methoxyethyl)-21H,23H-porphine-13,17-dipropionate (1) and pheophorbide a (2), inhibited TNF-α-induced ICAM-1 expression and decreased the TNF-α-induced transcription of ICAM-1, vascular cell adhesion molecule-1, and E-selectin genes. 1 and 2 reduced the expression of the NF-κB subunit RelA protein for 1 h, which was not rescued by the inhibition of proteasome- and lysosome-dependent protein degradation. In addition, 1 and 2 decreased the expression of multiple components of the TNF receptor 1 complex, and this was accompanied by the appearance of their cross-linked forms. As common components of the NF-κB signaling pathway, 1 and 2 also cross-linked the α, β, and γ subunits of the inhibitor of NF-κB kinase complex and the NF-κB subunits RelA and p50. Cellular protein synthesis was prevented by 2, but not by 1. Therefore, the present results indicate that porphyrin derivative 1 reduced the expression and increased the cross-linked forms of cellular components required for the NF-κB signaling pathway without affecting global protein synthesis.

01 Aug 2024·Journal of Cellular Physiology

The miR‐29‐3p family suppresses inflammatory osteolysis

Article

Author: Shin, Bongjin ; Karki, Sangita ; Hrdlicka, Henry C ; Delany, Anne M ; Lee, Sun-Kyeong ; Fraser, Brianna

AbstractOsteoclasts are the cells primarily responsible for inflammation‐induced bone loss, as is particularly seen in rheumatoid arthritis. Increasing evidence suggests that osteoclasts formed under homeostatic versus inflammatory conditions may differ in phenotype. While microRNA‐29‐3p family members (miR‐29a‐3p, miR‐29b‐3p, miR‐29c‐3p) promote the function of RANKL‐induced osteoclasts, the role of miR‐29‐3p during inflammatory TNF‐α‐induced osteoclastogenesis is unknown. We used bulk RNA‐seq, histology, qRT‐PCR, reporter assays, and western blot analysis to examine bone marrow monocytic cell cultures and tissue from male mice in which the function of miR‐29‐3p family members was decreased by expression of a miR‐29‐3p tough decoy (TuD) competitive inhibitor in the myeloid lineage (LysM‐cre). We found that RANKL‐treated monocytic cells expressing the miR‐29‐3p TuD developed a hypercytokinemia/proinflammatory gene expression profile in vitro, which is associated with macrophages. These data support the concept that miR‐29‐3p suppresses macrophage lineage commitment and may have anti‐inflammatory effects. In correlation, when miR‐29‐3p activity was decreased, TNF‐α‐induced osteoclast formation was accentuated in an in vivo model of localized osteolysis and in a cell‐autonomous manner in vitro. Further, miR‐29‐3p targets mouse TNF receptor 1 (TNFR1/Tnfrsf1a), an evolutionarily conserved regulatory mechanism, which likely contributes to the increased TNF‐α signaling sensitivity observed in the miR‐29‐3p decoy cells. Whereas our previous studies demonstrated that the miR‐29‐3p family promotes RANKL‐induced bone resorption, the present work shows that miR‐29‐3p dampens TNF‐α‐induced osteoclastogenesis, indicating that miR‐29‐3p has pleiotropic effects in bone homeostasis and inflammatory osteolysis. Our data supports the concept that the knockdown of miR‐29‐3p activity could prime myeloid cells to respond to an inflammatory challenge and potentially shift lineage commitment toward macrophage, making the miR‐29‐3p family a potential therapeutic target for modulating inflammatory response.

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TRAP1

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