Role of PTHrP nuclear localization and carboxyl terminus sequences in postnatal spinal cord development

Liu, Yahong; Wang, Qiangcheng; Wang, Qun; Cui, Min; Jin, Yaoyao; Wang, Rong; Mao, Zhiyuan; Miao, Dengshun; Karaplis, Andrew C.; Shields, Lisa B. E.; Shields, Christopher B.; Zhang, Yongjie

doi:10.1002/dneu.22798

Cited by 2 publications

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References 52 publications

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“…Bone morphogenetic protein 2 (BMP2) facilitated osteogenic differen-tiation in dental follicle stem cells via endogenous expression of PTHrP ( 8 ). Moreover, repression of PTHrP expression in neural stem cells (NSCs) inhibited prolifera-tion and differentiation and promoted apoptosis ( 9 ). PTHrP is essential not only for stem cells but also for different types of tumor cell progression.…”

Section: Introductionmentioning

confidence: 99%

Parathyroid Hormone-Related Protein Promotes the Proliferation of Patient-Derived Glioblastoma Stem Cells via Activating cAMP/PKA Signaling Pathway

et al. 2023

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Background and Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its heterogeneity and high recurrence and lethality rates. Glioblastoma stem cells (GSCs) play a crucial role in therapy resistance and tumor recurrence. Therefore, targeting GSCs is a key objective in developing effective treatments for GBM. The role of Parathyroid hormone-related peptide (PTHrP) in GBM and its impact on GSCs remains unclear. This study aimed to investigate the effect of PTHrP on GSCs and its potential as a therapeutic target for GBM. Methods and Results: Using the Cancer Genome Atlas (TCGA) database, we found higher expression of PTHrP in GBM, which correlated inversely with survival. GSCs were established from three human GBM samples obtained after surgical resection. Exposure to recombinant human PTHrP protein (rPTHrP) at different concentrations significantly enhanced GSCs viability. Knockdown of PTHrP using target-specific siRNA (siPTHrP) inhibited tumorsphere formation and reduced the number of BrdU-positive cells. In an orthotopic xenograft mouse model, suppression of PTHrP expression led to significant inhibition of tumor growth. The addition of rPTHrP in the growth medium counteracted the antiproliferative effect of siPTHrP. Further investigation revealed that PTHrP increased cAMP concentration and activated the PKA signaling pathway. Treatment with forskolin, an adenylyl cyclase activator, nullified the antiproliferative effect of siPTHrP. Conclusions: Our findings demonstrate that PTHrP promotes the proliferation of patient-derived GSCs by activating the cAMP/PKA signaling pathway. These results uncover a novel role for PTHrP and suggest its potential as a therapeutic target for GBM treatment.

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Section: Introductionmentioning

confidence: 99%

Parathyroid Hormone-Related Protein Promotes the Proliferation of Patient-Derived Glioblastoma Stem Cells via Activating cAMP/PKA Signaling Pathway

et al. 2023

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CaSR modulates proliferation of the superficial zone cells in temporomandibular joint cartilage via the PTHrP nuclear localization sequence

et al. 2023

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The superficial zone cells in mandibular condylar cartilage are proliferative. The present purpose was to delineate the relation of calcium‐sensing receptor (CaSR) and parathyroid hormone‐related peptide nuclear localization sequence (PTHrP87‐139), and their role in the proliferation behaviors of the superficial zone cells. A gain‐ and loss‐of‐function strategy were used in an in vitro fluid flow shear stress (FFSS) model and an in vivo bilateral elevation bite model which showed mandibular condylar cartilage thickening. CaSR and PTHrP87‐139 were modulated through treating the isolated superficial zone cells with activator/SiRNA and via deleting CaSR or parathyroid hormone‐related peptide (PTHrP) gene in mice with the promoter gene of proteoglycan 4 (Prg4‐CreERT2) in the tamoxifen‐inducible pattern with or without additional injection of Cinacalcet, the CaSR agonist, or PTHrP87‐139 peptide. FFSS stimulated CaSR and PTHrP expression, and accelerated proliferation of the Prg4‐expressing superficial zone cells, in which process CaSR acted as an up‐streamer of PTHrP. Proteoglycan 4 specific knockout of CaSR or PTHrP reduced the cartilage thickness, suppressed the proliferation and early differentiation of the superficial zone cells, and inhibited cartilage thickening and matrix production promoted by bilateral elevation bite. Injections of CaSR agonist Cinacalcet could not improve the phenotype caused by PTHrP mutation. Injections of PTHrP87‐139 peptide rescued the cartilage from knockout of CaSR gene. CaSR modulates proliferation of the superficial zone cells in mandibular condylar cartilage through activation of PTHrP nuclear localization sequence. Our data support the therapeutic target of CaSR in promoting PTHrP production in superficial zone cartilage.

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Role of PTHrP nuclear localization and carboxyl terminus sequences in postnatal spinal cord development

Cited by 2 publications

References 52 publications

Parathyroid Hormone-Related Protein Promotes the Proliferation of Patient-Derived Glioblastoma Stem Cells via Activating cAMP/PKA Signaling Pathway

Parathyroid Hormone-Related Protein Promotes the Proliferation of Patient-Derived Glioblastoma Stem Cells via Activating cAMP/PKA Signaling Pathway

CaSR modulates proliferation of the superficial zone cells in temporomandibular joint cartilage via the PTHrP nuclear localization sequence

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