Multi-Faceted Roles of DNAJB Protein in Cancer Metastasis and Clinical Implications

Kim, Hye-Youn

doi:10.3390/ijms232314970

Cited by 14 publications

(10 citation statements)

References 119 publications

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“…As such non-native, aggregation-prone folds are typical clients of molecular chaperones, we screened for JDPs that specifically recognize and then prevent the misfolding and aggregation of two destabilizing, cancer-associated hot-spot p53 mutants - R249S and R282W. Four main classes of JDPs, previously reported to affect cancer progression, were tested: class A (DNAJA1 and DNAJA2), class B (DNAJB1 and DNAJB4), non-canonical class B (DNAJB2 and DNAJB6), and class C (DNAJC7 and DNAJC8) chaperones 3, 13, 14 .…”

Section: Resultsmentioning

confidence: 99%

“…Conformational p53 oncogenic mutants are misfolding-prone clients of the chaperone system. Specifically, several JDP family members were described to promote cancer by acting on these destabilized mutant proteins, preventing p53 ubiquitination and degradation 3, 13, 14 . Here we identified a previously uncharacterized client binding domain in class A JDPs, which can recognize the initial stages of misfolding in p53 mutants and, via direct interaction, stabilize the β-sheet rich DNA-binding domain in these oncoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence indicates direct involvement of different JDP family members in cancer, with both tumor-suppressive and oncogenic roles reported 3,13,14 . Specifically, several cancerassociated conformational (destabilized) p53 mutants have been shown to interact with JDP chaperones 3 .…”

Section: Introductionmentioning

confidence: 99%

“…The p53 tumor suppressor protein is a known cellular client of the human Hsp70 chaperone system, which regulates its conformational stability and prevents p53 ubiquitination and degradation 11,12 . Increasing evidence indicates direct involvement of different JDP family members in cancer, with both tumor-suppressive and oncogenic roles reported 3,13,14 . Specifically, several cancer-associated conformational (destabilized) p53 mutants have been shown to interact with JDP chaperones 3 .…”

Section: Introductionmentioning

confidence: 99%

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A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

Zoltsman,

Dang,

Kuchersky

et al. 2023

Preprint

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SUMMARYJ-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here we uncover a novel mechanism by which chaperones recognize misfolded clients, present in class-A JDPs. Through a newly-identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class-A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class-A JDP β-hairpin as a highly specific target for cancer therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

Zoltsman,

Dang,

Kuchersky

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Further, we demonstrated that miR‐23a‐3p bound to DNAJB1 complementally. DNAJB1, located at 19p13.2, plays an important role in protein translation, folding/refolding, transport, and degradation 27 . DNAJB1‐PRKACA fusion transcripts are considered to be oncogenic drivers of fibrolamellar hepatocellular carcinoma 28 .…”

Section: Discussionmentioning

confidence: 99%

MiR‐23a‐3p alleviates cigarette smoke extract‐induced pulmonary vascular endothelial cell apoptosis by targeting DNAJB1 in emphysema

Li,

Ye,

et al. 2023

Clinical Respiratory J

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BackgroundCigarette smoke (CS) is an important risk factor for chronic obstructive pulmonary disease, including emphysema. MicroRNAs (miRNAs) are important regulators of emphysema progression. However, miR‐23a‐3p role in emphysema is unclear.MethodsCS exposure was used to construct emphysema mice models, and cigarette smoke extract (CSE)‐induced pulmonary vascular endothelial cells (PMVECs) were used to mimic emphysema cell models. Mouse lung tissue was stained by immunohistochemical staining, hematoxylin and eosin staining, and TUNEL staining. MiR‐23a‐3p and DnaJ homolog subfamily B member 1 (DNAJB1) levels were tested using quantitative real‐time PCR. DNAJB1 and apoptosis‐related markers' protein levels were examined via western blot analysis. Cell viability and apoptosis were analyzed by MTT assay and flow cytometry. The interaction between miR‐23a‐3p and DNAJB1 was evaluated by dual‐luciferase reporter assay and RIP assay.ResultsMiR‐23a‐3p was downregulated, and DNAJB1 was upregulated in CS‐induced emphysema mice models and CSE‐induced PMVECs. MiR‐23a‐3p overexpression promoted viability and repressed apoptosis in CSE‐induced PMVECs. MiR‐23a‐3p targeted DNAJB1 and negatively regulated DNAJB1 expression. Moreover, DNAJB1 knockdown repressed CSE‐induced PMVECs apoptosis, and miR‐23a‐3p inhibitor reversed this effect. Additionally, miR‐23a‐3p alleviated lung tissue injury and improved emphysema in mice by reducing DNAJB1 expression.ConclusionMiR‐23a‐3p alleviated emphysema progression, which could inhibit CSE‐induced PMVECs apoptosis by targeting DNAJB1.

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Phylloquinone improves endothelial function, inhibits cellular senescence, and vascular inflammation

Kieronska-Rudek,

Kij,

Bar

et al. 2024

GeroScience

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Phylloquinon (PK) and menaquinones (MK) are both naturally occurring compounds belonging to vitamin K group. Present study aimed to comprehensively analyze the influence of PK in several models of vascular dysfunction to determine whether PK has vasoprotective properties, similar to those previously described for MK. Effects of PK and MK on endothelial dysfunction were studied in ApoE/LDLR−/− mice in vivo, in the isolated aorta incubated with TNF, and in vascular cells as regard inflammation and cell senescence (including replicative and stress-induced models of senescence). Moreover, the vascular conversion of exogenous vitamins to endogenous MK-4 was analyzed. PK, as well as MK, given for 8 weeks in diet (10 mg/kg) resulted in comparable improvement in endothelial function in the ApoE/LDLR−/− mice. Similarly, PK and MK prevented TNF-induced impairment of endothelium-dependent vasorelaxation in the isolated aorta. In in vitro studies in endothelial and vascular smooth muscle cells, we identified that both PK and MK displayed anti-senescence effects via decreasing DNA damage while in endothelial cells anti-inflammatory activity was ascribed to the modulation of NFκB activation. The activity of PK and MK was comparable in terms of their effect on senescence and inflammation. Presence of endogenous synthesis of MK-4 from PK in aorta and endothelial and smooth muscle cells suggests a possible involvement of MK in vascular effects of PK. In conclusion, PK and MK display comparable vasoprotective effects, which may be ascribed, at least in part, to the inhibition of cell senescence and inflammation. The vasoprotective effect of PK in the vessel wall can be related to the direct effects of PK, as well as to the action of MK formed from PK in the vascular wall.

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Multi-Faceted Roles of DNAJB Protein in Cancer Metastasis and Clinical Implications

Cited by 14 publications

References 119 publications

A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

MiR‐23a‐3p alleviates cigarette smoke extract‐induced pulmonary vascular endothelial cell apoptosis by targeting DNAJB1 in emphysema

Phylloquinone improves endothelial function, inhibits cellular senescence, and vascular inflammation

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