suppressor function
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2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Beatriz Sanchez-Solana ◽  
Dunrui Wang ◽  
Xiaolan Qian ◽  
Parthibane Velayoudame ◽  
Dhirendra K. Simanshu ◽  
...  

Abstract Background DLC1, a tumor suppressor gene that is downregulated in many cancer types by genetic and nongenetic mechanisms, encodes a protein whose RhoGAP and scaffolding activities contribute to its tumor suppressor functions. The role of the DLC1 START (StAR-related lipid transfer; DLC1-START) domain, other than its binding to Caveolin-1, is poorly understood. In other START domains, a key function is that they bind lipids, but the putative lipid ligand for DLC1-START is unknown. Methods Lipid overlay assays and Phosphatidylserine (PS)-pull down assays confirmed the binding of DLC1-START to PS. Co-immunoprecipitation studies demonstrated the interaction between DLC1-START and Phospholipase C delta 1 (PLCD1) or Caveolin-1, and the contribution of PS to those interactions. Rho-GTP, cell proliferation, cell migration, and/or anchorage-independent growth assays were used to investigate the contribution of PS and PLCD1, or the implications of TCGA cancer-associated DLC1-START mutants, to DLC1 functions. Co-immunoprecipitations and PS-pull down assays were used to investigate the molecular mechanisms underlying the impaired functions of DLC1-START mutants. A structural model of DLC1-START was also built to better understand the structural implications of the cancer-associated mutations in DLC1-START. Results We identified PS as the lipid ligand for DLC1-START and determined that DLC1-START also binds PLCD1 protein in addition to Caveolin-1. PS binding contributes to the interaction of DLC1 with Caveolin-1 and with PLCD1. The importance of these activities for tumorigenesis is supported by our analysis of 7 cancer-associated DLC1-START mutants, each of which has reduced tumor suppressor function but retains wildtype RhoGAP activity. Our structural model of DLC1-START indicates the mutants perturb different elements within the structure, which is correlated with our experimental findings that the mutants are heterogenous with regard to the deficiency of their binding properties. Some have reduced PS binding, others reduced PLCD1 and Caveolin-1 binding, and others are deficient for all of these properties. Conclusion These observations highlight the importance of DLC1-START for the tumor suppressor function of DLC1 that is RhoGAP-independent. They also expand the versatility of START domains, as DLC1-START is the first found to bind PS, which promotes the binding to other proteins.


Haematologica ◽  
2021 ◽  
Author(s):  
Matthew J. Christopher ◽  
Casey D. S. Katerndahl ◽  
Hayley R. LeBlanc ◽  
Tyler T. Elmendorf ◽  
Vaishali Basu ◽  
...  

Not available.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ling-Chih Chen ◽  
Yung-Lin Hsieh ◽  
Grace Y. T. Tan ◽  
Tai-Yun Kuo ◽  
Yu-Chi Chou ◽  
...  

AbstractPosttranslational modification (PTM) of core circadian clock proteins, including Period2 (PER2), is required for proper circadian regulation. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs or their interaction with PER2 phosphorylation. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had different effects on PER2 turnover and transcriptional suppressor function. SUMO2 conjugation facilitated PER2 interaction with β-TrCP leading to PER2 proteasomal degradation. In contrast, SUMO1 conjugation, mediated by E3 SUMO-protein ligase RanBP2, enhanced CK1-mediated PER2S662 phosphorylation, inhibited PER2 degradation and increased PER2 transcriptional suppressor function. PER2 K736 was critical for both SUMO1- and SUMO2-conjugation. A PER2K736R mutation was sufficient to alter PER2 protein oscillation and reduce PER2-mediated transcriptional suppression. Together, our data revealed that SUMO1 versus SUMO2 conjugation acts as a determinant of PER2 stability and function and thereby affects the circadian regulatory system and the expression of clock-controlled genes.


2021 ◽  
Author(s):  
Antje Repenning ◽  
Daniela Happel ◽  
Caroline Bouchard ◽  
Marion Meixner ◽  
Yesim Verel‐Yilmaz ◽  
...  

2021 ◽  
Vol 22 (7) ◽  
pp. 3457
Author(s):  
Shalu Sharma ◽  
Antara Sengupta ◽  
Shantanu Chowdhury

The metastasis suppressor function of NM23 proteins is widely understood. Multiple enzymatic activities of NM23 proteins have also been identified. However, relatively less known interesting aspects are being revealed from recent developments that corroborate the telomeric interactions of NM23 proteins. Telomeres are known to regulate essential physiological events such as metastasis, ageing, and cellular differentiation via inter-connected signalling pathways. Here, we review the literature on the association of NM23 proteins with telomeres or telomere-related factors, and discuss the potential implications of emerging telomeric functions of NM23 proteins. Further understanding of these aspects might be instrumental in better understanding the metastasis suppressor functions of NM23 proteins.


Neoplasia ◽  
2021 ◽  
Vol 23 (1) ◽  
pp. 129-139
Author(s):  
Wenmei Lu ◽  
Qian Wang ◽  
Ci Xu ◽  
Haihua Yuan ◽  
Qiang Fan ◽  
...  

2020 ◽  
pp. canres.1804.2020
Author(s):  
Ning Kon ◽  
Michael Churchill ◽  
Huan Li ◽  
Siddhartha Mukherjee ◽  
James J. Manfredi ◽  
...  

2020 ◽  
Vol 44 (6) ◽  
pp. 328-355
Author(s):  
Birkan GİRGİN ◽  
Medine KARADAĞ-ALPASLAN ◽  
Fatih KOCABAŞ

MEIS proteins are historically associated with tumorigenesis, metastasis, and invasion in cancer. MEIS and associated PBX-HOX proteins may act as tumor suppressors or oncogenes in different cellular settings. Their expressions tend to be misregulated in various cancers. Bioinformatic analyses have suggested their upregulation in leukemia/lymphoma, thymoma, pancreas, glioma, and glioblastoma, and downregulation in cervical, uterine, rectum, and colon cancers. However, every cancer type includes, at least, a subtype with high MEIS expression. In addition, studies have highlighted that MEIS proteins and associated factors may function as diagnostic or therapeutic biomarkers for various diseases. Herein, MEIS proteins and associated factors in tumorigenesis are discussed with recent discoveries in addition to how they could be modulated by noncoding RNAs or newly developed small-molecule MEIS inhibitors.


Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2677
Author(s):  
Pooja A. Shah ◽  
Chenfei Huang ◽  
Qiuli Li ◽  
Sawad A. Kazi ◽  
Lauren A. Byers ◽  
...  

Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1’s role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer’s genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.


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