A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury

Kim, Ji Young; Bai, Yuntao; Jayne, Laura A.; Hector, Ralph D.; Persaud, Avinash K.; Ong, Su Sien; Rojesh, Shreshtha; Raj, Radhika; Feng, Mei; Chung, Sangwoon; Cianciolo, Rachel E.; Christman, John W.; Campbell, Moray J.; Gardner, David; Baker, Sharyn D.; Sparreboom, Alex; Govindarajan, Rajgopal; Singh, Harpreet; Chen, Taosheng; Poi, Ming; Suszták, Katalin; Cobb, Stuart; Pabla, Navjotsingh

doi:10.1038/s41467-020-15638-6

Cited by 47 publications

(65 citation statements)

References 71 publications

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“…A previous study (39) also described Vgf gene induction during IRI, however, its functional role in the pathogenesis remained unknown. We find that RTEC-specific Vgf deletion markedly In the current study, we find that Vgf deficiency exacerbates AKI, a phenotype that is similar to the RTEC-specific Sox9 deficient mice (31). However, Sox9 is a crucial transcriptional regulator of not only the early pathogenic phase (31), but also the later recovery phase of AKI (38,40).…”

Section: Discussionsupporting

confidence: 65%

“…We find that RTEC-specific Vgf deletion markedly In the current study, we find that Vgf deficiency exacerbates AKI, a phenotype that is similar to the RTEC-specific Sox9 deficient mice (31). However, Sox9 is a crucial transcriptional regulator of not only the early pathogenic phase (31), but also the later recovery phase of AKI (38,40). Sox9 expressing RTECs are involved in the repair and regeneration processes post-AKI (38,40).…”

Section: Discussionsupporting

confidence: 65%

“…6A). Sox9 is upregulated in RTECs in response to injury and is a critical transcriptional regulator of epithelial cell fate during AKI (31,(38)(39)(40)(41). To test the hypothesis that Sox9 is involved in Vgf upregulation during AKI, we performed promoter-driven luciferase-based reporter assays ( Fig.…”

Section: Vgf Regulation By Sox9 In the Early Acute Phase Of Renal Injmentioning

confidence: 99%

“…Trypan blue staining and MTT assay was used to determine cellular viability as reported in our previous study (31). BUMPT, HK-2 cells or RTECs were seeded in 6-well, 24-well, or 96-well plates, followed by cisplatin treatment for 24-48 h. At the end of the incubation period, cells from 6-well plates were harvested, followed by trypan blue staining and manual cell counting with a hemocytometer and/or by using Countess Automated Cell Counter (Thermo Fisher); translucent cells were considered as viable and blue-stained cells were counted as dead.…”

Section: Cell Viability and Caspase Assaysmentioning

confidence: 99%

“…The half-maximal inhibitory concentration (IC50) was calculated by nonlinear regression analysis using GraphPad Prism. The mT/mG mice were bred with Ggt1-Cre strain.as reported previously (31). For all mouse colonies, the pups were ear tagged and genotyped at 3 weeks of age.…”

Section: Cell Viability and Caspase Assaysmentioning

confidence: 99%

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SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in kidney epithelial cells

Kim¹,

Bai²,

Jayne³

et al. 2020

Preprint

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AbstractAcute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. In patients with sepsis, rhabdomyolysis, cancer, as well as cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxic, cytotoxic, and inflammatory insults to renal tubular epithelial cells (RTECs) resulting in the onset of AKI. To uncover stress-responsive disease-modifying genes, here we have carried out renal transcriptome profiling in three distinct murine models of AKI. We find that Vgf nerve growth factor inducible gene upregulation is a common transcriptional stress response in RTECs to ischemia, cisplatin, and rhabdomyolysis-associated renal injury. The Vgf gene encodes a secretory peptide precursor protein that has critical neuro-endocrine functions; however, its role in the kidneys remains unknown. Our functional studies show that RTEC-specific Vgf gene ablation exacerbates ischemia, cisplatin, and rhabdomyolysis-associated AKI in vivo and cisplatin-induced RTEC cell death in vitro. Importantly, addback experiments showed that aggravation of cisplatin-induced renal injury caused by Vgf gene ablation is partly reversed by TLQP-21, a Vgf-derived peptide. Finally, in vitro and in vivo mechanistic studies showed that injury-induced Vgf upregulation in RTECs is driven by the transcriptional regulator Sox9. These findings reveal a crucial downstream target of the Sox9-directed transcriptional program and identify Vgf as a stress-responsive protective gene in kidney epithelial cells.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionsupporting

confidence: 65%

Section: Vgf Regulation By Sox9 In the Early Acute Phase Of Renal Injmentioning

confidence: 99%

Section: Cell Viability and Caspase Assaysmentioning

confidence: 99%

Section: Cell Viability and Caspase Assaysmentioning

confidence: 99%

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SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in kidney epithelial cells

Kim¹,

Bai²,

Jayne³

et al. 2020

Preprint

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Thieno[3,2‐b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode

Moyano,

Kubina,

Paruch

et al. 2024

Angewandte Chemie

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Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2‐b]pyridine scaffold. The weak interaction of the thieno[3,2‐b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome‐wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP‐competitive but not ATP‐mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2‐b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in cancer cells. The thieno[3,2‐b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting other underexplored protein kinases, such as CDKLs.

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Thieno[3,2‐b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode

Moyano,

Kubina,

Paruch

et al. 2024

Angew Chem Int Ed

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A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury

Cited by 47 publications

References 71 publications

SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in kidney epithelial cells

SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in kidney epithelial cells

Thieno[3,2‐b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode

Thieno[3,2‐b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode

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