scholarly journals Hypoxia stimulates SUMOylation-dependent stabilization of KDM5B

2021 ◽  
Author(s):  
Bingluo Zhou ◽  
Yiran Zhu ◽  
Wenxia Xu ◽  
Qiyin Zhou ◽  
Linghui Tan ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Tumor Hypoxia ◽  
Protein Stabilization ◽  
Tumor Xenograft ◽  
Cyclin Dependent Kinase ◽  
Normal Tissues ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Lysine Specific Demethylase

Abstract Background Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress through activating a series of adaption response. The study on the mechanism of tumor hypoxia adaption is still of urgent significance to find effective therapeutic targets and strategies. Methods We compared the protein expression of KDM5B in tumor or normal tissues and cell lines by IHC and Western blotting (WB). CCK8 and cell colony formation assay was performed to evaluate the KDM5B caused growth inhibition. The transcriptome analysis, quantitative real-time PCR (qPCR), flow cytometry analysis, chromatin immunoprecipitation (ChIP) were for exploring the downstream mechanism. And the SUMOylation assay and Ni-beads pull-down assay and co-immunoprecipitation (co-IP) were used to illustrate how did post-translation modification (PTM) regulate the KDM5B protein stabilization. Finally, tumor xenograft assay in nude mice verified the findings in vivo. Results We found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia condition. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Inhibition of KDM5B caused significant cell cycle G1/S arrest through the transcription upregulation of cyclin-dependent kinase inhibitor 1 (CDKN1, also known as p21). Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase which increased the interaction with KDM5B under hypoxia condition. As the result, co-targeting KDM5B significantly improved the anti-tumor efficacy of antiangiogenic therapy in vivo. Conclusion Taken together, PIAS4 mediated SUMOylation stabilized KDM5B protein through disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia adaption. Targeting SUMOylation-dependent KDM5B upregulation might be considered when antiangiogenic therapy was applied in cancer treatment.

Functional Loss of p21/Waf-1 in a Case of Benign Canine Multicentric Melanoma

1998 ◽  
Vol 35 (2) ◽  
pp. 94-101 ◽  
Author(s):  
M. G. Ritt ◽  
J. Wojcieszyn ◽  
J. F. Modiano
Keyword(s):  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
P53 Gene ◽  
Tumor Formation ◽  
Cyclin Dependent Kinase ◽  
P53 Expression ◽  
Functional Loss ◽  
Normal Tissues ◽  
Cyclin Dependent Kinase Inhibitor

Mutations of tumor suppressor genes remove mechanisms that normally arrest proliferation of transformed cells, resulting in tumor formation. The p53 gene product functions as a tumor suppressor that induces p21/Waf-1, the 21-kDa product of the waf-1/cip-1/mda-6 gene. p21/Waf-1 is a pan-cyclin-dependent kinase inhibitor that arrests cell cycle progression under a variety of circumstances. We examined tissues from a dog with multiple primary pigmented proliferative lesions (benign, multicentric melanoma consisting of three distinct dermal lesions and a matrical cyst) for p21/Waf-1 and p53 expression by immunohistochemistry and immunoblotting. p21/Waf-1 and p-53 proteins were undetectable in the tumor cells and in the cyst but were present in adjacent normal tissues. Abundant cyclin-dependent kinase 4 (Cdk4), a protein related functionally to p21/Waf-1, also was present in the cyst. A somatic mutation of the waf-1 gene or of the p53 gene may have resulted in the loss of p21/Waf-1 expression in a common precursor of pigment-producing cells from the affected dog. Furthermore, this functional loss of p21/Waf-1 may play an important role in the genesis of canine benign melanoma.

scholarly journals Negative Regulation of ASK1 by p21Cip1 Involves a Small Domain That Includes Serine 98 That Is Phosphorylated by ASK1 In Vivo

2007 ◽  
Vol 27 (9) ◽  
pp. 3530-3541 ◽  
Author(s):  
Jun Zhan ◽  
John B. Easton ◽  
Shile Huang ◽  
Ashutosh Mishra ◽  
Limin Xiao ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cellular Functions ◽  
Terminal Protein ◽  
Jnk Pathway ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Small Domain ◽  
Cellular Stresses

ABSTRACT The cyclin-dependent kinase inhibitor p21Cip1 regulates multiple cellular functions and protects cells from genotoxic and other cellular stresses. Activation of apoptosis signal-regulating kinase 1 (ASK1) induced by inhibition of mTOR signaling leads to sustained phospho-c-Jun that is suppressed in cells with functional p53 or by forced expression of p21Cip1. Here we show that small deletions of p21Cip1 around S98 abrogate its association with ASK1 but do not affect binding to Cdk1, hence distinguishing between the cell cycle-regulating functions of p21Cip1 and its ability to suppress activation of the ASK1/Jun N-terminal protein kinase (JNK) pathway. p21Cip1 is phosphorylated in vitro by both ASK1 and JNK1 at S98. In vivo phosphorylation of p21Cip1, predominantly carried out by ASK1, is associated with binding to ASK1 and inactivation of ASK1 kinase function. Binding of p21Cip1 to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98.

scholarly journals Therapeutic targeting of tumor-associated myeloid cells synergizes with radiation therapy for glioblastoma

2019 ◽  
Vol 116 (47) ◽  
pp. 23714-23723 ◽  
Author(s):  
Peng Zhang ◽  
Jason Miska ◽  
Catalina Lee-Chang ◽  
Aida Rashidi ◽  
Wojciech K. Panek ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Clinical Response ◽  
Kinase Inhibitor ◽  
Myeloid Cells ◽  
Cyclin Dependent Kinase ◽  
Therapeutic Modalities ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Programmed Death ◽  
Immense Potential

Tumor-associated myeloid cells (TAMCs) are key drivers of immunosuppression in the tumor microenvironment, which profoundly impedes the clinical response to immune-dependent and conventional therapeutic modalities. As a hallmark of glioblastoma (GBM), TAMCs are massively recruited to reach up to 50% of the brain tumor mass. Therefore, they have recently been recognized as an appealing therapeutic target to blunt immunosuppression in GBM with the hope of maximizing the clinical outcome of antitumor therapies. Here we report a nano-immunotherapy approach capable of actively targeting TAMCs in vivo. As we found that programmed death-ligand 1 (PD-L1) is highly expressed on glioma-associated TAMCs, we rationally designed a lipid nanoparticle (LNP) formulation surface-functionalized with an anti–PD-L1 therapeutic antibody (αPD-L1). We demonstrated that this system (αPD-L1-LNP) enabled effective and specific delivery of therapeutic payload to TAMCs. Specifically, encapsulation of dinaciclib, a cyclin-dependent kinase inhibitor, into PD-L1–targeted LNPs led to a robust depletion of TAMCs and an attenuation of their immunosuppressive functions. Importantly, the delivery efficiency of PD-L1–targeted LNPs was robustly enhanced in the context of radiation therapy (RT) owing to the RT-induced up-regulation of PD-L1 on glioma-infiltrating TAMCs. Accordingly, RT combined with our nano-immunotherapy led to dramatically extended survival of mice in 2 syngeneic glioma models, GL261 and CT2A. The high targeting efficiency of αPD-L1-LNP to human TAMCs from GBM patients further validated the clinical relevance. Thus, this study establishes a therapeutic approach with immense potential to improve the clinical response in the treatment of GBM and warrants a rapid translation into clinical practice.

The p21 cyclin–dependent kinase inhibitor suppresses tumorigenicity in vivo

1995 ◽  
Vol 1 (10) ◽  
pp. 1052-1056 ◽  
Author(s):  
Zhi-Yong Yang ◽  
Neil D. Perkins ◽  
Takeshi Ohno ◽  
Elizabeth G. Nabel ◽  
Gary J. Nabel
Keyword(s):  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor

scholarly journals Combination Gene Delivery of the Cell Cycle Inhibitor p27 with Thymidine Kinase Enhances Prodrug Cytotoxicity

1998 ◽  
Vol 72 (11) ◽  
pp. 9201-9207 ◽  
Author(s):  
Xavier Danthinne ◽  
Kazunori Aoki ◽  
Akiko L. Kurachi ◽  
Gary J. Nabel ◽  
Elizabeth G. Nabel
Keyword(s):  
Cell Cycle ◽  
Gene Transfer ◽  
Thymidine Kinase ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Genetically Modified ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor

ABSTRACT Cytoxicity induced by the herpesvirus thymidine kinase (TK) gene in combination with prodrugs is dependent on cell growth and leads to the elimination of genetically modified cells, thus limiting the duration of expression and efficacy of this treatment in vivo. Here, an effort was made to enhance TK/prodrug efficacy by coexpression of a cyclin-dependent kinase inhibitor (CKI), p27, to render cells resistant to TK/prodrug by inhibiting DNA synthesis. Expression of p27 by transfection substantially reduced cell cycle progression, and its activity was enhanced by mutations designed to stabilize the protein. Coexpression of p27 and TK or a p27/TK fusion protein led to greater prodrug cytotoxicity than that produced by TK alone in the Renca cell line, which is sensitive to bystander killing. Combination gene transfer of this CKI with TK therefore sustained the synthesis of TK by genetically modified cells to enhance the susceptibility of bystander cells to prodrug cytotoxicity and increased the efficacy of this gene transfer approach.

Sign in / Sign up

Export Citation Format

Share Document