scholarly journals Regulation of Skp2 Expression and Activity and Its Role in Cancer Progression

2010 ◽  
Vol 10 ◽  
pp. 1001-1015 ◽  
Author(s):  
Chia-Hsin Chan ◽  
Szu-Wei Lee ◽  
Jing Wang ◽  
Hui-Kuan Lin
Keyword(s):  
Cell Cycle ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Protein Levels ◽  
Human Cancers ◽  
Attractive Therapeutic Target ◽  
Skp2 Protein ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

The regulation of cell cycle entry is critical for cell proliferation and tumorigenesis. One of the key players regulating cell cycle progression is the F-box protein Skp2. Skp2 forms a SCF complex with Skp1, Cul-1, and Rbx1 to constitute E3 ligase through its F-box domain. Skp2 protein levels are regulated during the cell cycle, and recent studies reveal that Skp2 stability, subcellular localization, and activity are regulated by its phosphorylation. Overexpression of Skp2 is associated with a variety of human cancers, indicating that Skp2 may contribute to the development of human cancers. The notion is supported by various genetic mouse models that demonstrate an oncogenic activity of Skp2 and its requirement in cancer progression, suggesting that Skp2 may be a novel and attractive therapeutic target for cancers.

scholarly journals Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases

2020 ◽  
Vol 52 (10) ◽  
pp. 1637-1651 ◽  
Author(s):  
Sang-Min Jang ◽  
Christophe E. Redon ◽  
Bhushan L. Thakur ◽  
Meriam K. Bahta ◽  
Mirit I. Aladjem
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Ubiquitin Ligases ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

Abstract The last decade has revealed new roles for Cullin-RING ubiquitin ligases (CRLs) in a myriad of cellular processes, including cell cycle progression. In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cell cycle, it is now evident that all eight CRL family members are involved in the intricate cellular pathways driving cell cycle progression. In this review, we summarize the structure of CRLs and their functions in driving the cell cycle. We focus on how CRLs target key proteins for degradation or otherwise alter their functions to control the progression over the various cell cycle phases leading to cell division. We also summarize how CRLs and the anaphase-promoting complex/cyclosome (APC/C) ligase complex closely cooperate to govern efficient cell cycle progression.

Phosphorylation of Runx1 by Cyclin-Dependent Kinases Regulates Its Interaction with HDAC1 and HDAC3.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1381-1381 ◽  
Author(s):  
Hong Guo ◽  
Alan D. Friedman
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Cyclin D3 ◽  
Mrna Levels ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Protein Levels ◽  
Cdk Phosphorylation ◽  
Regulation Of Cell Cycle

Abstract Runx1/AML1 is a key regulator of hematopoiesis and leukemic transformation, as RUNX1(−/−) mice do not develop definitive hematopoietic stem cells, and sever alleukemic oncogenes, e.g. AML1-ETO, CBFβ-SMMHC, or TEL-AML1, inhibit Runx1activities. We have investigated regulation of cell cycle progression by Runx1. Runx1stimulates G1 to S cell cycle progression in hematopoietic cell lines and in transduced myeloid progenitors, and inhibition of Runx1 by CBFβ-SMMHC or AML1-ETO slows G1 progression. Runx1 induces cdk4 and cyclin D3 transcription, and exogenous cdk4, cyclin D2, or c-Myc overcomes inhibition of G1 progression by CBF oncoproteins. In addition to regulating cell cycle progression, Runx1 protein levels are themselves increased as hematopoietic cells progress from G1 to S to G2/M, though mRNA levels remain constant. Runx1 contains three consensus cdk sites, (S/T)PX(R/K), S48, S303, and S424, and using phospho-specific antisera we find that each of these is modified in hematopoietic cells. Mutation of these serines to aspartic acid, mimicking phosphorylation, increases trans-activation of a reporter containing four CBF sites or the TCRβ promoter, whereas mutation to alanine reduces trans-activation. p300 interacts similarly with Runx1(tripleA) and Runx1(tripleD). We have now evaluated interaction of HDACs1–8 with these variants and Runx1 and find that both HDAC1 and HDAC3 have reduced affinity for RUNX1(tripleD), as assessed by co-immunoprecipitation from transiently transfected 293T cells. Evaluation of single serine residue mutants (S48D, S303D, and S424D) demonstrates reduced affinity of HDAC1 or HDAC3 specifically for the Runx1(S424D) mutant, consistent with previous mapping of the Runx1:HDAC1 and Runx1:HDAC3 interactions to this region of Runx1. Thus, cdk phosphorylation of Runx1 S424 reduces affinity for HDAC1 and HDAC3, increasing Runx1 trans-activation potency. Regulation of Runx1 activity by cdks may control key developmental processes, including expansion of definitive HSC during development and regulation of the balance between adult HSC quiescence and proliferation.

PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

2019 ◽  
Vol 26 (11) ◽  
pp. 800-818
Author(s):  
Zujian Xiong ◽  
Xuejun Li ◽  
Qi Yang
Keyword(s):  
Cell Cycle ◽  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Cell Cycle Progression ◽  
Key Factors ◽  
Cycle Progression ◽  
Sister Chromatids ◽  
Regulation Of Cell Cycle ◽  
Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

scholarly journals Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanne Fransson ◽  
Angela Martinez-Monleon ◽  
Mathias Johansson ◽  
Rose-Marie Sjöberg ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Mapk Signaling ◽  
Telomere Maintenance ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Cycle Progression

AbstractNeuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

Estrogen Regulation of Cell Cycle Progression

2001 ◽  
pp. 220-227
Author(s):  
Owen W. J. Prall ◽  
Eileen M. Rogan ◽  
Elizabeth A. Musgrove ◽  
Colin K. W. Watts ◽  
Robert L. Sutherland
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Estrogen Regulation ◽  
Cycle Progression ◽  
Regulation Of Cell Cycle
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