Olfactomedin 4 regulates migration and proliferation of immortalized non-transformed keratinocytes through modulation of the cell cycle machinery and actin cytoskeleton remodelling

Cárdenas-León, Claudia Griselda; Klaas, Mariliis; Mäemets-Allas, Kristina; Arak, Terje; Eller, Mart; Jaks, Viljar

doi:10.1016/j.yexcr.2022.113111

Cited by 7 publications

(7 citation statements)

References 57 publications

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“…Accordingly, Cdk1 and Cdk2 have been shown to phosphorylate both S164 and T170 (which does not match even the partial CDK consensus, S/T-P) in vitro 4,29,31,53 . Studies that describe changes in Cdk7 T-loop phosphorylation upon different perturbations often report concomitant deregulation of the cell cycle 32,34,54 . However, whether the observed changes in Cdk7 T-loop phosphorylation occurred as a consequence or cause of cell-cycle deregulation was not clearly determined.…”

Section: Discussionmentioning

confidence: 99%

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Structural basis of Cdk7 activation by dual T-loop phosphorylation

Düster,

Anand,

Binder

et al. 2024

Preprint

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Cyclin-dependent kinase 7 (Cdk7) occupies a central position in cell-cycle and transcriptional regulation owing to its function as both a CDK-activating kinase (CAK) and part of the general transcription factor TFIIH. Cdk7 forms an active complex upon association with Cyclin H and Mat1, and its catalytic activity is regulated by two phosphorylations in the activation segment (T loop): the canonical activating modification at T170 and another at S164. Here we report the crystal structure of the fully activated human Cdk7/Cyclin H/Mat1 complex containing both T-loop phosphorylations. Whereas pT170 coordinates a set of basic residues conserved in other CDKs, pS164 nucleates an arginine network involving all three subunits that is unique to the ternary Cdk7 complex. We identify differential dependencies of kinase activity and substrate recognition on individual phosphorylations within the Cdk7 T loop. The CAK function of Cdk7 is not affected by T-loop phosphorylation, whereas activity towards non-CDK substrates is increased several-fold by phosphorylation at T170. Moreover, dual T-loop phosphorylation at both T170 and S164 stimulates multi-site phosphorylation of transcriptional substrates, the RNA polymerase II (RNAPII) carboxy-terminal domain (CTD) and the SPT5 carboxy-terminal repeat (CTR) region. In human cells, Cdk7-regulatory phosphorylation is a two-step process in which phosphorylation of S164 precedes, and may prime, T170 phosphorylation. Thus, dual T-loop phosphorylation can regulate Cdk7 through multiple mechanisms, with pS164 supporting tripartite complex formation and possibly influencing Cdk7 processivity, while the canonical pT170 enhances kinase activity towards critical substrates involved in transcription.

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Section: Discussionmentioning

confidence: 99%

“…d , Radiometric kinase assay to analyze the inhibitory potential of VHH RD7-01 . Assay was performed as in c but with varying concentrations of VHH RD7-01 and with 1 mM ATP containing 0.35 µCi 32 [P]γ-ATP. Cdk9/CycT1 1-272 was used as a control for nanobody specificity.…”

Section: Supplementary Informationmentioning

confidence: 99%

Structural basis of Cdk7 activation by dual T-loop phosphorylation

Düster,

Anand,

Binder

et al. 2024

Preprint

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“…In vitro and in vivo experiments are needed to investigate whether JMJD1C regulates IS via adipogenesis or not. As for WAS, it encodes WASP and participates in acting network assembly [51], which is also associated with cell behaviors [52][53][54], however, how it functions in IS are not elucidated. In addition, we also try to explain the molecular mechanisms of those biomarkers by bioinformatic analysis.…”

Section: Discussionmentioning

confidence: 99%

Machine learning identifies novel coagulation genes as diagnostic and immunological biomarkers in ischemic stroke

Liu,

Si,

Liu

et al. 2024

Aging

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Background: Coagulation system is currently known associated with the development of ischemic stroke (IS). Thus, the current study is designed to identify diagnostic value of coagulation genes (CGs) in IS and to explore their role in the immune microenvironment of IS. Methods: Aberrant expressed CGs in IS were input into unsupervised consensus clustering to classify IS subtypes. Meanwhile, key CGs involved in IS were further selected by weighted gene co-expression network analysis (WGCNA) and machine learning methods, including random forest (RF), support vector machine (SVM), generalized linear model (GLM) and extreme-gradient boosting (XGB). The diagnostic performance of key CGs were evaluated by receiver operating characteristic (ROC) curves. At last, quantitative PCR (qPCR) was performed to validate the expressions of key CGs in IS. Results: IS patients were classified into two subtypes with different immune microenvironments by aberrant expressed CGs. Further WGCNA, machine learning methods and ROC curves identified ACTN1, F5, TLN1, JMJD1C and WAS as potential diagnostic biomarkers of IS. In addition, their expressions were significantly correlated with macrophages, neutrophils and/or T cells. GSEA also revealed that those biomarkers may regulate IS via immune and inflammation. Moreover, qPCR verified the expressions of ACTN1, F5 and JMJD1C in IS. Conclusions: The current study identified ACTN1, F5 and JMJD1C as novel coagulation-related biomarkers associated with IS immune microenvironment, which enriches our knowledge of coagulation-mediated pathogenesis of IS and sheds light on next-step in vivo and in vitro experiments to elucidate the relevant molecular mechanisms.

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“…Sweat glands from DC tissue samples ( n = 9) and sweat glands isolated from normal palmar skin ( n = 9) were denatured, alkylated, and digested as previously described [ 41 ]. Samples were injected into Thermo ScientificTM DionexTM UltimateTM 3000 RSLCnano systems equipped with NCS-3500RS (microflow) module and Q Exactive Plus—OrbitrapTM spectrometer (Thermo Fisher Scientific) operated in Data-Independent Acquisition (DIA) mode for peptide and protein quantification.…”

Section: Methodsmentioning

confidence: 99%

Proteomic Analysis of Dupuytren’s Contracture-Derived Sweat Glands Revealed the Synthesis of Connective Tissue Growth Factor and Initiation of Epithelial-Mesenchymal Transition as Major Pathogenetic Events

Cárdenas-León

Mäemets-Allas

Klaas

et al. 2023

IJMS

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Dupuytren’s contracture (DC) is a chronic and progressive fibroproliferative disorder restricted to the palmar fascia of the hands. Previously, we discovered the presence of high levels of connective tissue growth factor in sweat glands in the vicinity of DC nodules and hypothesized that sweat glands have an important role in the formation of DC lesions. Here, we shed light on the role of sweat glands in the DC pathogenesis by proteomic analysis and immunofluorescence microscopy. We demonstrated that a fraction of sweat gland epithelium underwent epithelial-mesenchymal transition illustrated by negative regulation of E-cadherin. We hypothesized that the increase in connective tissue growth factor expression in DC sweat glands has both autocrine and paracrine effects in sustaining the DC formation and inducing pathological changes in DC-associated sweat glands.

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Olfactomedin 4 regulates migration and proliferation of immortalized non-transformed keratinocytes through modulation of the cell cycle machinery and actin cytoskeleton remodelling

Cited by 7 publications

References 57 publications

Structural basis of Cdk7 activation by dual T-loop phosphorylation

Structural basis of Cdk7 activation by dual T-loop phosphorylation

Machine learning identifies novel coagulation genes as diagnostic and immunological biomarkers in ischemic stroke

Proteomic Analysis of Dupuytren’s Contracture-Derived Sweat Glands Revealed the Synthesis of Connective Tissue Growth Factor and Initiation of Epithelial-Mesenchymal Transition as Major Pathogenetic Events

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