Multipotent neurogenic fate of mesenchymal stem cell is determined by Cdk4-mediated hypophosphorylation of Smad-STAT3

Kim, Dong‐Young; Lee, Janet; Kang, Dongrim; Lee, Dohyeong; Kim, Yoon-Ja; Hwang, Sang‐Gu; Kim, Dong Ik; Lee, Chang-Woo; Lee, Kyung-Hoon

doi:10.1080/15384101.2016.1188230

Cited by 5 publications

(3 citation statements)

References 36 publications

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“…In the present study, we showed miR-145 reduced SMAD3 expression in vitro and in vivo, along with the decrease of Cdk4/Cyclin D1 and XIAP. The results were consistent with the previous report that Cdk4 inhibition dephosphorylated Smads (28). The results suggested that miR-145 worked as a tumor suppressor in acquired regorafenib-resistant colon cancer cells.…”

Section: Discussionsupporting

confidence: 93%

Long Non-coding RNA MIR570MG Causes Regorafenib Resistance in Colon Cancer by Repressing miR-145/SMAD3 Signaling

Fang

Wang

et al. 2020

Front. Oncol.

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An increasing number of studies have shown that long non-coding RNA (lncRNA) dysregulation plays a fundamental role in the development of various cancers, including colon cancer. Nonetheless, the mechanisms of lncRNA in regorafenib-resistance remain unclear. Our research revealed the lncRNA MIR570MG increased in regorafenib-resistant colon cancer cells compared to the regorafenib-sensitive cells. Furthermore, MIR570MG sponged miR-145, which declined in regorafenib-resistant colon cancer cell lines. More importantly, overexpression of miR-145 hampered cell proliferation and retrieved colon cancer regorafenib-sensitivity, contrary to the function of MIR570MG. Dual-luciferase reporter assay confirmed that miR-145 bound to 3 ′-UTR of SMAD3, a transcriptional modulator activated by TGFβ, resulting in blockage of TGFβ /SMAD3-mediated cell growth and cycle progression. Besides, ectopic expression of miR-145 inhibitor in the parental cells endowed resistance to regorafenib. Inversely, knockdown of MIR570MG impoverished resistance against regorafenib. Additionally, overexpression of MIR570MG conquered the suppression of tumor growth by miR-146 and rehabilitated the resistance to regorafenib in HCT116R human colon cancer mouse models. In summary, our findings suggested that MIR570MG promoted regorafenib resistance via releasing SMAD3 from miR-145, leading to activation of SMAD3-mediated signaling pathways.

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Section: Discussionsupporting

confidence: 93%

Long Non-coding RNA MIR570MG Causes Regorafenib Resistance in Colon Cancer by Repressing miR-145/SMAD3 Signaling

Fang

Wang

et al. 2020

Front. Oncol.

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“…A previous study showed that CDK4 inhibition directly inactivated Smad1/5/9 and subsequently dephosphorylated STAT3 in human mesenchymal stem cells [ 14 ]. However, our study found that palbociclib had no influence on Smad1/5/9 phosphorylation in H520 and H226 cells ( Figure 4 A and Figure S6 ).…”

Section: Resultsmentioning

confidence: 99%

Palbociclib Induces the Apoptosis of Lung Squamous Cell Carcinoma Cells via RB-Independent STAT3 Phosphorylation

Xiang

et al. 2022

Current Oncology

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Lung squamous cell carcinoma (LUSC) treatment response is poor and treatment alternatives are limited. Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, has recently been approved for hormone receptor-positive breast cancer patients and applied in multiple preclinical models, but its use for LUSC therapy remains elusive. Here, we investigated whether palbociclib induced cell apoptosis and dissected the underlying mechanism in LUSC. We found that palbociclib induced LUSC cell apoptosis through inhibition of Src tyrosine kinase/signal transducers and activators of transcription 3 (STAT3). Interestingly, palbociclib reduced STAT3 signaling in LUSC cells interfered by retinoblastoma tumor-suppressor gene (RB), suggesting that pro-apoptosis effect of palbociclib was independent of classic CDK4/6-RB signaling. Furthermore, palbociclib could suppress IL-1β and IL-6 expression, and therefore blocked Src/STAT3 signaling, which were rescued by either recombinant human IL-1β or IL-6. Moreover, Myc mediated the sensitivity of LUSC cells to palbociclib. Our discoveries demonstrated that palbociclib induces apoptosis of LUSC cells through the Src/STAT3 axis in an RB-independent manner, and provided a reliable experimental basis of clinical studies in LUSC patients.

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“…Several Cdk kinases contain additional motifs in addition to the kinase domain for functional relevance: Cdk12/Cdk13(PITAIRE) 42,43 , Cdk14/Cdk15(PFTAIRE) 23,44 , and Cdk16/Cdk17/Cdk18 (PCTAIRE) [45][46][47] . In addition to their role in the cell cycle, Cdks coordinate with stemness 48 , cell polarity 49,50 , and cell fate specification/determination [51][52][53][54] . Cdk16 (also known as PCTAIRE-1) was previously reported to participate in secretory cargo transport 55 , autophagy 28 , spermatogenesis 28,56 , and tumor proliferation 57 .…”

Section: Discussionmentioning

confidence: 99%

A phosphorylation switch of Huluwa receptor for embryonic axis induction

Chen,

Li,

Yan

et al. 2024

Preprint

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Embryonic axis formation is essential for patterning and morphogenesis in vertebrates and is tightly regulated by the dorsal organizer. Previously, we demonstrated that maternally derived Huluwa (Hwa) acts as a dorsal determinant, dictating axis formation by activating β-catenin signaling in zebrafish and Xenopus. However, the mechanism of activation and fine regulation of the Hwa receptor remain unclear. In a systematic mutation screen, a mutation at the 168th serine (Ser168) in the PPNSP motif of Hwa dramatically abolished its axis-inducing activity. Mechanistically, mutating the Ser168 residue reduced its binding affinity to Tankyrase 1/2 and the degradation of the Axin protein, weakening β-catenin signaling activation. Furthermore, the Ser168 site was confirmed to be phosphorylated via LC-MS/MS and immunoblotting with a phosphorylation-specific antibody. Additionally, several kinases, including Cdk16, Cdk2, and GSK3β, were found to enhance Ser168 phosphorylation in vitro and in vivo, enhancing Hwa's activity in β-catenin signaling and axis induction. Meanwhile, the use of dominant-negative Cdk16 and pHwa (Ser168) antibodies reduced Hwa's function. In summary, Ser168 acts as a phosphorylation switch in Hwa/β-catenin signaling for embryonic axis induction, involving multiple kinases to ensure developmental robustness.

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Multipotent neurogenic fate of mesenchymal stem cell is determined by Cdk4-mediated hypophosphorylation of Smad-STAT3

Cited by 5 publications

References 36 publications

Long Non-coding RNA MIR570MG Causes Regorafenib Resistance in Colon Cancer by Repressing miR-145/SMAD3 Signaling

Long Non-coding RNA MIR570MG Causes Regorafenib Resistance in Colon Cancer by Repressing miR-145/SMAD3 Signaling

Palbociclib Induces the Apoptosis of Lung Squamous Cell Carcinoma Cells via RB-Independent STAT3 Phosphorylation

A phosphorylation switch of Huluwa receptor for embryonic axis induction

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