Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration

Lampropoulou, Evgenia; Logoviti, Ioanna; Κουτσιούμπα, Μαρίνα; Hatziapostolou, Maria; Polytarchou, Christos; Skandalis, Spyros S.; Hellman, Ulf; Fousteris, Manolis A.; Nikolaropoulos, Sotiris S.; Choleva, Efrosini; Lamprou, Margarita; Skoura, Angeliki; Megalooikonomou, Vasileios; Papadimitriou, Evangelia

doi:10.1038/s41598-018-24326-x

Cited by 16 publications

(10 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results obtained from the migration assay show a response from the ECs similar to the one obtained for the viability assay. As shown in Figure 5, the H/P gels were able to induce a significant increase in the migration of the treated HUVECs compare to control conditions, confirming the beneficial effects of PTN on ECs migration (Lampropoulou et al, 2018; Copes et al, 2019). Interesting, contrary to the H/P gels, the effect exerted by the P150 gels resulted being not significantly higher compared to the control conditions, further validating the hypothesis of a protective/enhancing effect of heparin on PTN activity toward ECs.…”

Section: Discussionsupporting

confidence: 66%

Heparin-Modified Collagen Gels for Controlled Release of Pleiotrophin: Potential for Vascular Applications

Copes

Chevallier

Loy

et al. 2019

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

A fast re-endothelialization, along with the inhibition of neointima hyperplasia, are crucial to reduce the failure of vascular bypass grafts. Implants modifications with molecules capable of speeding up the re-endothelialization process have been proposed over the last years. However, clinical trials of angiogenic factor delivery have been mostly disappointing, underscoring the need to investigate a wider array of angiogenic factors. In this work, a drug release system based on a type I collagen hydrogel has been proposed for the controlled release of Pleiotrophin (PTN), a cytokine known for its pro-angiogenetic effects. Heparin, in virtue of its ability to sequester, protect and release growth factors, has been used to better control the release of PTN. Performances of the PTN drug delivery system on endothelial (ECs) and smooth muscle cells (SMCs) have been investigated. Structural characterization (mechanical tests and immunofluorescent analyses of the collagen fibers) was performed on the gels to assess if heparin caused changes in their mechanical behavior. The release of PTN from the different gel formulations has been analyzed using a PTN-specific ELISA assay. Cell viability was evaluated with the Alamar Blue Cell Viability Assay on cells directly seeded on the gels (direct test) and on cells incubated with supernatant, containing the released PTN, obtained from the gels (indirect test). The effects of the different gels on the migration of both ECs and SMCs have been evaluated using a Transwell migration assay. Hemocompatibility of the gel has been assessed with a clotting/hemolysis test. Structural analyses showed that heparin did not change the structural behavior of the collagen gels. ELISA quantification demonstrated that heparin induced a constant release of PTN over time compared to other conditions. Both direct and indirect viability assays showed an increase in ECs viability while no effects were noted on SMCs. Cell migration results evidenced that the heparin/PTN-modified gels significantly increased ECs migration and decreased the SMCs one. Finally, heparin significantly increased the hemocompatibility of the collagen gels. In conclusion, the PTN-heparin-modified collagen here proposed can represent an added value for vascular medicine, able to ameliorate the biological performance, and integration of vascular grafts.

show abstract

Section: Discussionsupporting

confidence: 66%

Heparin-Modified Collagen Gels for Controlled Release of Pleiotrophin: Potential for Vascular Applications

Copes

Chevallier

Loy

et al. 2019

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

show abstract

“…Furthermore, during angiogenesis, pleiotrophin can motivate endothelial migration via binding with receptor protein tyrosine phosphatase beta/zeta and ανβ3 integrin. CDK5 activation in the modulation of angiogenic migration of endothelium is mediated by pleiotrophin-receptor protein tyrosine phosphatase beta/zeta signaling [35]. Otherwise, CDK1, a well-known cell cycle and apoptosis regulator, was reported to be overexpressed in pathological retinal angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study

Shi

Kuo

Chen

et al. 2019

Cells

View full text Add to dashboard Cite

Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human cancers. In this study, we investigated the role and therapeutic potential of CDK7 in regulating the angiogenic activity of endothelial cells and human renal cell carcinoma (RCC). Our results revealed that vascular endothelial growth factor (VEGF), a critical activator of angiogenesis, upregulated the expression of CDK7 and RNAPII, and the phosphorylation of RNAPII at serine 5 and 7 in human umbilical vein endothelial cells (HUVECs), indicating the transcriptional activity of CDK7 may be involved in VEGF-activated angiogenic activity of endothelium. Furthermore, through suppressing CDK7 activity, THZ1 suppressed VEGF-activated proliferation and migration, as well as enhanced apoptosis of HUVECs. Moreover, THZ1 inhibited VEGF-activated capillary tube formation and CDK7 knockdown consistently diminished tube formation in HUVECs. Additionally, THZ1 reduced VEGF expression in human RCC cells (786-O and Caki-2), and THZ1 treatment inhibited tumor growth, vascularity, and angiogenic marker (CD31) expression in RCC xenografts. Our results demonstrated that CDK7-mediated transcription was involved in the angiogenic activity of endothelium and human RCC. THZ1 suppressed VEGF-mediated VEGFR2 downstream activation of angiogenesis, providing a new perspective for antitumor therapy in RCC patients.

show abstract

“…Accordingly, pleiotrophin (PTN) is a secreted growth factor that stimulates human endothelial cell migration by binding to receptor proteins tyrosine phosphatase beta/zeta (RPTP β/ζ) and ανβ3 integrin. CDK5 mediates the PTN-induced movement of endothelial cells [ 180 , 181 ]. CDK5 also promotes the stabilisation and transcriptional activity of hypoxia-inducible factor-1α (HIF-1α) through the phosphorylation of HIF-1α at Ser687, thus accelerating the formation of blood vessel [ 182 ].…”

Section: The Role Of Cdk5 In Cancer Cellsmentioning

confidence: 99%

The Role of CDK5 in Tumours and Tumour Microenvironments

Anh

Lee

2020

Cancers

View full text Add to dashboard Cite

Cyclin-dependent kinase 5 (CDK5), which belongs to the protein kinase family, regulates neuronal function but is also associated with cancer development and has been proposed as a target for cancer treatment. Indeed, CDK5 has roles in cell proliferation, apoptosis, angiogenesis, inflammation, and immune response. Aberrant CDK5 activation triggers tumour progression in numerous types of cancer. In this review, we summarise the role of CDK5 in cancer and neurons and CDK5 inhibitors. We expect that our review helps researchers to develop CDK5 inhibitors as treatments for refractory cancer.

show abstract

Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration

Cited by 16 publications

References 54 publications

Heparin-Modified Collagen Gels for Controlled Release of Pleiotrophin: Potential for Vascular Applications

Heparin-Modified Collagen Gels for Controlled Release of Pleiotrophin: Potential for Vascular Applications

Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study

The Role of CDK5 in Tumours and Tumour Microenvironments

Contact Info

Product

Resources

About