Hsp70–Bag3 Module Regulates Macrophage Motility and Tumor Infiltration via Transcription Factor LITAF and CSF1

Avinery, Elena; Gahramanov, Valid; Hesin, Arkadi; Sherman, Michael Y.

doi:10.3390/cancers14174168

Cited by 9 publications

(9 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this context, the results of the present study showing lysosomal degradation of CDIP1 provide supporting evidence that CDIP1 is a membrane-integrated protein. On the other hand, for LITAF, a paralog of CDIP1, some reported data indicate that it is degraded mainly by lysosomes [ 16 ], while other data suggest that both the lysosomal and proteasomal pathways are involved in its degradation [ 48 ]. Differences in degradation pathways may reflect differences in the membrane-localized proportions of LITAF proteins or may result from differences in experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells

Inukai,

Mori,

Maki

et al. 2024

IJMS

View full text Add to dashboard Cite

Cell death-inducing p53-target protein 1 (CDIP1) is a proapoptotic protein that is normally expressed at low levels and is upregulated by genotoxic and endoplasmic reticulum stresses. CDIP1 has been reported to be localized to endosomes and to interact with several proteins, including B-cell receptor-associated protein 31 (BAP31) and apoptosis-linked gene 2 (ALG-2). However, the cellular and molecular mechanisms underlying CDIP1 expression-induced apoptosis remain unclear. In this study, we first demonstrated that CDIP1 was upregulated after treatment with the anticancer drug adriamycin in human breast cancer MCF-7 cells but was degraded rapidly in the lysosomal pathway. We also demonstrated that treatment with the cyclin-dependent kinase 5 (CDK5) inhibitor roscovitine led to an increase in the electrophoretic mobility of CDIP1. In addition, a phosphomimetic mutation at Ser-32 in CDIP1 resulted in an increase in CDIP1 expression-induced apoptosis. We also found that CDIP1 expression led to the induction of autophagy prior to apoptosis. Treatment of cells expressing CDIP1 with SAR405, an inhibitor of the class III phosphatidylinositol 3-kinase VPS34, caused a reduction in autophagy and promoted apoptosis. Therefore, autophagy is thought to be a defense mechanism against CDIP1 expression-induced apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells

Inukai,

Mori,

Maki

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

“…Previous research on BAG3 mostly focused on the correlation between BAG3 mutation and genetic diseases such as dilated cardiomyopathy [31][32][33]. With the incremental understanding on BAG3, its various roles as a molecular chaperone have been gradually discovered [34,35]. In addition, numerous studies have shown that BAG3 plays an indispensable role in autophagy and cell survival by bridging multiple signaling pathways [9,11,12,22].…”

Section: Discussionmentioning

confidence: 99%

BAG3 promotes proliferation and migration of arterial smooth muscle cells by regulating STAT3 phosphorylation in diabetic vascular remodeling

Huang,

Guo,

Ning

et al. 2024

Cardiovasc Diabetol

View full text Add to dashboard Cite

Background Diabetic vascular remodeling is the most important pathological basis of diabetic cardiovascular complications. The accumulation of advanced glycation end products (AGEs) caused by elevated blood glucose promotes the proliferation and migration of vascular smooth muscle cells (VSMCs), leading to arterial wall thickening and ultimately vascular remodeling. Therefore, the excessive proliferation and migration of VSMCs is considered as an important therapeutic target for vascular remodeling in diabetes mellitus. However, due to the lack of breakthrough in experiments, there is currently no effective treatment for the excessive proliferation and migration of VSMCs in diabetic patients. Bcl-2-associated athanogene 3 (BAG3) protein is a multifunctional protein highly expressed in skeletal muscle and myocardium. Previous research has confirmed that BAG3 can not only regulate cell survival and apoptosis, but also affect cell proliferation and migration. Since the excessive proliferation and migration of VSMCs is an important pathogenesis of vascular remodeling in diabetes, the role of BAG3 in the excessive proliferation and migration of VSMCs and its molecular mechanism deserve further investigation. Methods In this study, BAG3 gene was manipulated in smooth muscle to acquire SM22αCre; BAG3FL/FL mice and streptozotocin (STZ) was used to simulate diabetes. Expression of proteins and aortic thickness of mice were detected by immunofluorescence, ultrasound and hematoxylin-eosin (HE) staining. Using human aorta smooth muscle cell line (HASMC), cell viability was measured by CCK-8 and proliferation was measured by colony formation experiment. Migration was detected by transwell, scratch experiments and Phalloidin staining. Western Blot was used to detect protein expression and Co-Immunoprecipitation (Co-IP) was used to detect protein interaction. Results In diabetic vascular remodeling, AGEs could promote the interaction between BAG3 and signal transducer and activator of transcription 3 (STAT3), leading to the enhanced interaction between STAT3 and Janus kinase 2 (JAK2) and reduced interaction between STAT3 and extracellular signal-regulated kinase 1/2 (ERK1/2), resulting in accumulated p-STAT3(705) and reduced p-STAT3(727). Subsequently, the expression of matrix metallopeptidase 2 (MMP2) is upregulated, thus promoting the migration of VSMCs. Conclusions BAG3 upregulates the expression of MMP2 by increasing p-STAT3(705) and decreasing p-STAT3(727) levels, thereby promoting vascular remodeling in diabetes. This provides a new orientation for the prevention and treatment of diabetic vascular remodeling.

show abstract

“…However, it is still unclear how UBR5 affects p53, which may be related to UBR5‐mediated ubiquitination and degradation (Song, Yeku, et al, 2020). Avinery et al (2022) found that the Hsp70‐Bag3 complex inhibits TAMs migration and infiltration by reducing CSF‐1 through UPS degradation of highly expressed transcription factor lipopolysaccharide TNF‐α factor (LITAF) in TAMs. A recent analysis showed that the core component of SKP1 cullin 1‐Fbox E3 ubiquitin ligase, FBXO1 (CCNF), FBXO20 (LMO7), FBXO22, FBXO28, FBXO32, and FBXO45 were generally negatively associated with TAMs infiltration (Zhang et al, 2022).…”

Section: Effect Of the Ups On Tamsmentioning

confidence: 99%

“…In a study of triple-negative breast cancer (TNBC), COP1 E3 was shown to bind to C/EBPδ via the linker protein Trib2 and to mediate the ubiquitinated degradation of C/EBPδ via UPS (Wang et al, 2021). C/EBPδ, a member of the CCAAT/enhancer binding protein (C/EBP) transcription factor family, acts as a tumor suppressor that not only induces cancer cell growth arrest and apoptosis (Balamurugan & Sterneck, 2013) but also inhibits the transcription of macrophage chemokines released from cancer cells.…”

Section: Cop1 (Constitutive Photomorphogenic 1 Also Known As Rfwd2)mentioning

confidence: 99%

Role of the ubiquitin–proteasome system on macrophages in the tumor microenvironment

Xiao,

Liu,

et al. 2024

Journal Cellular Physiology

View full text Add to dashboard Cite

Tumor‐associated macrophages (TAMs) are key components of the tumor microenvironment, and their different polarization states play multiple roles in tumors by secreting cytokines, chemokines, and so on, which are closely related to tumor development. In addition, the enrichment of TAMs is often associated with poor prognosis of tumors. Thus, targeting TAMs is a potential tumor treatment strategy, in which therapeutic approaches such as reducing TAMs numbers, remodeling TAMs phenotypes, and altering their functions are being extensively investigated. Meanwhile, the ubiquitin–proteasome system (UPS), an important mechanism of protein hydrolysis in eukaryotic cells, participates in cellular processes by regulating the activity and stability of key proteins. Interestingly, UPS plays a dual role in the process of tumor development, and its role in TAMs deserve to be investigated in depth. This review builds on this foundation to further explore the multiple roles of UPS on TAMs and identifies a promising approach to treat tumors by targeting TAMs with UPS.

show abstract

Hsp70–Bag3 Module Regulates Macrophage Motility and Tumor Infiltration via Transcription Factor LITAF and CSF1

Cited by 9 publications

References 77 publications

Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells

Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells

BAG3 promotes proliferation and migration of arterial smooth muscle cells by regulating STAT3 phosphorylation in diabetic vascular remodeling

Role of the ubiquitin–proteasome system on macrophages in the tumor microenvironment

Contact Info

Product

Resources

About