Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation

Кондакова, И. В.; Шашова, Е. Е.; Сиденко, Е. А.; Astakhova, T. Yu.; Захарова, Л. А.; Шарова, Н. П.

doi:10.3390/biom10040500

Cited by 25 publications

(21 citation statements)

References 127 publications

(154 reference statements)

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“…In addition to being potential prognostic biomarkers, components of the ubiquitinproteasome system (UPS) have been suggested to be potential candidates for targeted therapies against the ER [104]. This is due in part to previously identified associations between functions of these components and ER expression or activity.…”

Section: Ligand-independent Activation Of Erαmentioning

confidence: 99%

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Khatpe

Adebayo

Herodotou

et al. 2021

Cancers

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Signaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.

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Section: Ligand-independent Activation Of Erαmentioning

confidence: 99%

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Khatpe

Adebayo

Herodotou

et al. 2021

Cancers

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“…Tetraspanin-associated proteases include ADAM10, ADAM17, and matrix metalloproteinases (MMPs), tetraspanin-non-associated exosomal protease is 20S proteasome, PAPP-A etc. (Yunusova et al, 2018;Kondakova et al, 2020). ADAMs are multifunctional proteins that perform shedding that leads to the cleavage of the extracellular domain of transmembrane proteins (EGFR1, Her2, TGFbeta-IIIR, L1CAM, CD44, EpCAM) thereby regulating cell adhesion, migration, and intercellular interactions (Burbano et al, 2015).…”

Section: Exosomal Protease Cargo As Prognostic Biomarker In Colorectamentioning

confidence: 99%

Exosomal Protease Cargo as Prognostic Biomarker in Colorectal Cancer

Yunusova

Замбалова

Patysheva

et al. 2021

Asian Pac J Cancer Prev

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Objective: The aim of the study was to develop a model for predicting cancer risk in colorectal polyps' patients (CPPs), as well as to reveal additional prognosis factors for Stage III colorectal cancer based on differences in subpopulations of tetraspanins, tetraspanin-associated and tetraspanin-non-associated proteases in blood plasma exosomes of CPPs and colorectal cancer patients (CRCPs). Methods: The subpopulations of CD151-and Tspan8-positive exosomes, the subpopulations of metalloproteinase at the surface of СD9-positive exosomes and the level of 20S proteasomes in plasma exosomes in 15 CPPs (tubulovillous adenomas) and 60 CRCPs were evaluated using flow cytometry and Western blotting. Logistic regression analysis was performed to predict cancer risk of CPPs. Results: The levels of 20S proteasomes in exosomes, MMP9+, MMP9+/MMP2+/EMMPRIN+ in CD9-positive blood plasma exosomes are associated with the risk of malignant transformation of colorectal tubulovillous adenomas. In patients with Stage III CRC, the levels of 20S proteasomes (less than 2 units) and MMP9+ subpopulations (more than 61%) in plasma exosomes are unfavorable prognostic factors for overall survival. The levels of 20S proteasomes and ADAM10+/ ADAM17-subpopulations in CD9-positive blood plasma exosomes are the most significant values for predicting relapse-free survival. Conclusion: Protease cargo in CD9-positive blood plasma exosomes is prognostic biomarker for colorectal polyps and colorectal cancer.

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“…Particularly in the heart, these mechanisms appeared to implicate post-transcriptional modulation without involving global changes in autophagy or proteasome activity, at least as observed using the general markers of these processes. However, we cannot discard the possibility that estrogens might be activating or inhibiting these or other cellular processes in a more local or target-specific manner, since estrogens have been determined to finely tune the activation of the autophagic and proteasomal machinery in other tissue and cell types through their modulatory effects on different pathways [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones

Arcones

Martínez-Cignoni

Vila-Bedmar

et al. 2021

Cells

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Cardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes in G protein-coupled receptor kinase 2 (GRK2) protein levels in the murine heart and that mitochondrial fusion markers, related to mitochondrial functionality and cardiac health, inversely correlate with GRK2. Young female mice display lower amounts of cardiac GRK2 protein compared to age-matched males, whereas GRK2 is upregulated with age specifically in female hearts. Such an increase in GRK2 seems to be specific to the cardiac muscle since a different pattern is found in the skeletal muscles of aging females. Changes in the cardiac GRK2 protein do not seem to rely on transcriptional modulation since adrbk1 mRNA does not change with age and no differences are found between sexes. Global changes in proteasomal or autophagic machinery (known regulators of GRK2 dosage) do not seem to correlate with the observed GRK2 dynamics. Interestingly, cardiac GRK2 upregulation in aging females is recapitulated by ovariectomy and can be partially reversed by estrogen supplementation, while this does not occur in the skeletal muscle. Our data indicate an unforeseen role for ovarian hormones in the regulation of GRK2 protein levels in the cardiac muscle which correlates with the sex-dependent dynamics of CVD risk, and might have interesting therapeutic applications, particularly for post-menopausal women.

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Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation

Cited by 25 publications

References 127 publications

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Exosomal Protease Cargo as Prognostic Biomarker in Colorectal Cancer

Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones

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