DOCSLIB.ORG

Cyclins, Cdks, E2f, Skp2, and More at the First International RB Tumor Suppressor Meeting

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cyclins, Cdks, E2f, Skp2, and More at the First International RB Tumor Suppressor Meeting Published OnlineFirst July 7, 2010; DOI: 10.1158/0008-5472.CAN-10-0358 Published OnlineFirst on July 7, 2010 as 10.1158/0008-5472.CAN-10-0358 Meeting Report Cancer Research Cyclins, Cdks, E2f, Skp2, and More at the First International RB Tumor Suppressor Meeting Rod Bremner1,3,4 and Eldad Zacksenhaus2,4,5,6 Abstract The RB1 gene was cloned because its inactivation causes the childhood ocular tumor, retinoblastoma. It is widely expressed, inactivated in most human malignancies, and present in diverse organisms from mammals to plants. Initially, retinoblastoma protein (pRB) was linked to cell cycle regulation, but it also regulates se- nescence, apoptosis, autophagy, differentiation, genome stability, immunity, telomere function, stem cell bi- ology, and embryonic development. In the 23 years since the gene was cloned, a formal international symposium focused on the RB pathway has not been held. The “First International RB Tumor Suppressor Meeting” (Toronto, Canada, November 19-21, 2009) established a biennial event to bring experts in the field together to discuss how the RB family (“pocket proteins”), as well as its regulators and effectors, influence biology and human disease. We summarize major new breakthroughs and emerging trends presented at the meeting. Cancer Res; 70(15); OF1–5. ©2010 AACR. Introduction critical for growth, thus their prominent expression could sensitize human cone precursors to RB1 mutation and un- Twenty speakers gave presentations on an astonishingly derlie a cone precursor origin of retinoblastoma (3). Studies diverse array of topics, underscoring the central role of reti- to date do not rule out an alternative possibility, that tumors noblastoma protein (pRB) in human biology (1). We have might convert to a cone-like epigenetic state during neoplas- grouped these topics into the general areas of cancer, E2f tic transformation (2). Irrespective, the data raise exciting functions, other pRB effectors, and pRB regulators. Refer- new avenues for treatment. The role of nuclear receptors ences are limited to work published in the past year. or Mdm2 in mouse retinoblastoma is unknown, but these tu- mors arise from amacrine cells (or horizontal cells that con- vert to amacrine cells during neoplastic transformation), RB1 in Cancer which exhibit naturally high resistance to apoptosis. Mouse data exist on Mycn: David Macpherson (Carnegie Institution, Retinoblastoma tumors carry homozygous RB1 mutations Baltimore, Maryland) reported gain in ∼30 to 50% of tumors (see below for an intriguing exception), and can be modeled from Rb/p107 or Rb/p130 null retina, respectively, and focal, in mice by deleting Rb1 and one of its relatives p107 or p130 high-level amplifications in a smaller subset, suggesting nat- (2). pRB mediates cell cycle exit in differentiating retinal neu- ural Mycn levels in mouse retina are insufficient for transfor- rons, and in its absence E2f1 delays cell cycle exit. Which mation. Brenda Gallie (Ontario Cancer Institute, Toronto, neuron is tumor-prone, and why, is debated. David Cobrinik Canada) has found that 1.5% of retinoblastoma tumors lack (Memorial Sloan-Kettering Cancer Center, New York, New RB1 mutations, but show high MYCN amplification. Thus, York) showed that human retinoblastoma exploits cone pho- RB1 loss plus naturally high MYCN, or high MYCN alone toreceptor features, including high expression (not amplifica- (plus as yet unknown other changes), are oncogenic in the tion) of the proto-oncogenes MYCN and MDM2,andthe human retina, and Rb1 plus Rb1-relative loss and Mycn gain nuclear receptors TRB2 and RXRG (3). All four factors are are oncogenic in mouse retina. Retinoblastoma exhibits common post-RB1 genetic events. Authors' Affiliations: 1Toronto Western Research Institute, 2Toronto General Research Institute, 3University Health Network, Departments of Gallie found that retinoma, a senescent benign tumor replete Ophthalmology and Vision Science, 4Laboratory Medicine and with p16Ink4a and p130 protein and evident in ∼15% of retino- Pathobiology, 5Medicine, 6Medical Biophysics, University of Toronto, RB1 Toronto, Ontario, Canada blastoma samples, has a subset of post- events present in malignant tumors, arguing that the latter derives from the for- Corresponding Authors: Rod Bremner, Toronto Western Research Insti- tute, University Health Network, 399 Bathurst Street, Room Mc6-424, mer. A common region of gain on human 1q contains KIF14 Toronto, Ontario, Canada, M5T 2S8. Phone: 416-603-5865; Fax: 416- and MDM4, and Macpherson showed that the syntenic region, 603-5126; E-mail: [email protected] and Eldad Zacksenhaus, Toronto General Research Institute, University Health Network, 67 College also on mouse chromosome 1q, undergoes copy number in- Street, Room 407, Toronto, Ontario, Canada, M5G 2M1. Phone: 416-340- crease in retinoblastoma models. Removing one allele of the 4800-5106; Fax: 416-340-3453; E-mail: [email protected]. Mdm2 inhibitor p19ARF accelerated mouse retinoblastoma, doi: 10.1158/0008-5472.CAN-10-0358 and approximately half of these malignancies showed loss of ©2010 American Association for Cancer Research. heterozygosity. These and other studies suggest an important www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst July 7, 2010; DOI: 10.1158/0008-5472.CAN-10-0358 Bremner and Zacksenhaus role for the MDM2-p53 pathway in retinoblastoma progres- disorder in the hematopoietic system, but not leukemia. sion, even though p53 itself is never mutated. In summary, TKO mouse embryonic stem cells could differentiate into MYCN, the p14/19ARF-MDM2/MDM4-p53 axis, and KIF14 embryoid bodies, and only 5 to 10% of cells showed BrdU in- are key players after RB1 loss in both mouse and human corporation. In these differentiated TKO cells, some E2f tar- retinoblastoma. gets remained elevated, but others and Myc genes were Typically, RB1± individuals develop multiple tumors in down-regulated as effectively as in wild-type cells. TKO em- both eyes, but low penetrance mutations that partially dis- bryos survived until midgestation in the presence of a wild- able pRB cause fewer tumors. R661W is the best studied mu- type placenta. Thus, multiple TKO cell types have potent tation, and David Goodrich (Roswell Park Cancer Institute, backup mechanisms, likely explaining why oncogenic viral Buffalo, New York) is employing the knock-in equivalent he proteins bind many factors other than pocket proteins. developed (R654W) to model cancer in mice. For example, Laura Buttitta (Fred Hutchinson Cancer Research Center, R654W/− − − the Rb :p53 / prostate is better protected against tu- Seattle, Washington) also discussed extensive feedback con- −/− − − mor progression than the Rb :p53 / tissue. Some E2f tar- trols that prevent cell cycle abnormalities. Robust ectopic di- gets are equally deregulated in both genotypes, thus vision in differentiating Drosophila wing or eye cells requires protection must be through distinct E2f targets and/or E2f- perturbation of both Rb-E2f and Cdk2 pathways. Removing independent mechanisms. Goodrich has also developed an inhibitors or expressing activators from either side of the T epitope-tagged knock-in Rb1 allele that will be useful in equation has minimal effect, which is explained by feedback mapping the protein and genome-wide chromatin targets mechanisms, for example, whereas E2f induces cyclin A, it of pRB in vivo (4). also induces APC/C, which degrades cyclin A. Loss of heterozygosity and RB1 down-regulation are com- mon in basal-like breast cancer, a highly aggressive subtype, as well as in luminal tumors. Eldad Zacksenhaus (Toronto Surprising In vivo Functions of Activating E2fs in General Research Institute, Toronto, Canada) described a Dividing Cells new mouse model for basal-like breast cancer, based on con- ditional Rb1 inactivation in mammary epithelium.7 Interest- Rod Bremner (Toronto Western Research Institute, Toronto, ingly, loss of Rb1 alone (without loss of Rb1 relatives) is Canada) and Gustavo Leone (Ohio State University, Columbus, sufficient to induce mammary tumors, and p53 status dic- Ohio) discussed in vivo functions of the three activating E2fs tates tumor subtype. (E2f1-3), downstream targets of pRB. Typically, E2fs are RB1 is also inactivated in hepatocellular carcinoma (HCC). viewed as indispensable for cell division. Surprisingly, howev- Erik Knudsen (Kimmel Cancer Center, Philadelphia, Pennsyl- er, many cell types divide in vivo without E2f1-3 (7, 8). In retina, vania) discussed the unexpected finding that conditional Rb1 this finding was explained by the ability of Mycn to maintain deletion does not perturb quiescence in normal or regenerat- expression of E2f targets and repress Cdkn1a (p21Cip1; ref. 7). ing mouse hepatocytes (even adding p107 or p130 absence; Unexpectedly, E2f1-3 have a prosurvival role in dividing ref. 5). Although Rb1 loss also does not cause HCC, it en- cells, which seems counterintuitive given that high E2f1-3 le- hances chemically induced tumorigenesis (see ref. 5 and re- vels drive apoptosis through p53 and p53-independent ferences therein). The expression profile of pRB target genes means. In retina, survival is linked to E2f-dependent expres- predicts disease outcome in human liver cancer, and animal sion of Sirt1 and other deacetylases that constrain p53 (7). models are revealing the impact of cell cycle inhibitory com- Death of E2f1-3 null crypt progenitors is p53-independent
Load more

Recommended publications
  • The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression
    International Journal of Molecular Sciences Review The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression Tingting Zou and Zhenghong Lin * School of Life Sciences, Chongqing University, Chongqing 401331, China; [email protected] * Correspondence: [email protected] Abstract: The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), which activities are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins, CDK inhibitors (CKIs), other kinases and phosphatases. Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell cycle progression via recognition, interaction, and ubiquitination or deubiquitination of key proteins. The illegitimate degradation of tumor suppressor or abnormally high accumulation of oncoproteins often results in deregulation of cell proliferation, genomic instability, and cancer occurrence. In this review, we demonstrate the diversity and complexity of the regulation of UPS machinery of the cell cycle. A profound understanding of the ubiquitination machinery will provide new insights into the regulation of the cell cycle transition, cancer treatment, and the development of anti-cancer drugs. Keywords: cell cycle regulation; CDKs; cyclins; CKIs; UPS; E3 ubiquitin ligases; Deubiquitinases (DUBs) Citation: Zou, T.; Lin, Z. The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression. 1. Introduction Int. J. Mol. Sci. 2021, 22, 5754. https://doi.org/10.3390/ijms22115754 The cell cycle is a ubiquitous, complex, and highly regulated process that is involved in the sequential events during which a cell duplicates its genetic materials, grows, and di- Academic Editors: Kwang-Hyun Bae vides into two daughter cells.
    [Show full text]
  • Foxo3a Transcription Factor Is a Negative Regulator of Skp2 and Skp2 SCF Complex
    Oncogene (2013) 32, 78 --85 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc ORIGINAL ARTICLE Foxo3a transcription factor is a negative regulator of Skp2 and Skp2 SCF complex JWu1,2,4,5, S-W Lee2,3,5, X Zhang2,3, F Han2,3, S-Y Kwan2,3, X Yuan2, W-L Yang2,3, YS Jeong2,3, AH Rezaeian2, Y Gao2,3, Y-X Zeng1 and H-K Lin,2,3 Skp2 (S-phase kinase-associated protein-2) SCF complex displays E3 ligase activity and oncogenic activity by regulating protein ubiquitination and degradation, in turn regulating cell cycle entry, senescence and tumorigenesis. The maintenance of the integrity of Skp2 SCF complex is critical for its E3 ligase activity. The Skp2 F-box protein is a rate-limiting step and key factor in this complex, which binds to its protein substrates and triggers ubiquitination and degradation of its substrates. Skp2 is found to be overexpressed in numerous human cancers, which has an important role in tumorigenesis. The molecular mechanism by which the function of Skp2 and Skp2 SCF complex is regulated remains largely unknown. Here we show that Foxo3a transcription factor is a novel and negative regulator of Skp2 SCF complex. Foxo3a is found to be a transcriptional repressor of Skp2 gene expression by directly binding to the Skp2 promoter, thereby inhibiting Skp2 protein expression. Surprisingly, we found for the first time that Foxo3a also displays a transcription-independent activity by directly interacting with Skp2 and disrupting Skp2 SCF complex formation, in turn inhibiting Skp2 SCF E3 ligase activity and promoting p27 stability.
    [Show full text]
  • Coordinate Phosphorylation of Multiple Residues on Single AKT1 and AKT2 Molecules
    Oncogene (2014) 33, 3463–3472 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc ORIGINAL ARTICLE Coordinate phosphorylation of multiple residues on single AKT1 and AKT2 molecules H Guo1,6, M Gao1,6,YLu1, J Liang1, PL Lorenzi2, S Bai3, DH Hawke4,JLi1, T Dogruluk5, KL Scott5, E Jonasch3, GB Mills1 and Z Ding1 Aberrant AKT activation is prevalent across multiple human cancer lineages providing an important new target for therapy. Twenty- two independent phosphorylation sites have been identified on specific AKT isoforms likely contributing to differential isoform regulation. However, the mechanisms regulating phosphorylation of individual AKT isoform molecules have not been elucidated because of the lack of robust approaches able to assess phosphorylation of multiple sites on a single AKT molecule. Using a nanofluidic proteomic immunoassay (NIA), consisting of isoelectric focusing followed by sensitive chemiluminescence detection, we demonstrate that under basal and ligand-induced conditions that the pattern of phosphorylation events is markedly different between AKT1 and AKT2. Indeed, there are at least 12 AKT1 peaks and at least 5 AKT2 peaks consistent with complex combinations of phosphorylation of different sites on individual AKT molecules. Following insulin stimulation, AKT1 was phosphorylated at Thr308 in the T-loop and Ser473 in the hydrophobic domain. In contrast, AKT2 was only phosphorylated at the equivalent sites (Thr309 and Ser474) at low levels. Further, Thr308 and Ser473 phosphorylation occurred predominantly on the same AKT1 molecules, whereas Thr309 and Ser474 were phosphorylated primarily on different AKT2 molecules. Although basal AKT2 phosphorylation was sensitive to inhibition of phosphatidylinositol 3-kinase (PI3K), basal AKT1 phosphorylation was essentially resistant.
    [Show full text]
  • Basal P21 Controls Population Heterogeneity in Cycling and Quiescent Cell Cycle States
    Basal p21 controls population heterogeneity in cycling and quiescent cell cycle states K. Wesley Overtona, Sabrina L. Spencerb, William L. Noderera, Tobias Meyerb, and Clifford L. Wanga,1 Departments of aChemical Engineering and bChemical and Systems Biology, Stanford University, Stanford, CA 94305 Edited by Charles S. Peskin, New York University, Manhattan, NY, and approved August 27, 2014 (received for review May 27, 2014) Phenotypic heterogeneity within a population of genetically identical SCF/Skp2 then ubiquitinates p21, targeting it for proteasomal cells is emerging as a common theme in multiple biological systems, degradation (13). Thus, p21 both regulates and, through the ac- including human cell biology and cancer. Using live-cell imaging, flow tion of E3 ubiquitin ligase complexes that target p21, is regulated cytometry, and kinetic modeling, we showed that two states—quies- by active CDK2 bound to Cyclin E. cence and cell cycling—can coexist within an isogenic population of The p21–CDK2 control scheme is an example of a double- human cells and resulted from low basal expression levels of p21, a negative feedback loop. When stochastic gene expression leads Cyclin-dependent kinase (CDK) inhibitor (CKI). We attribute the p21- to fluctuations in factors involved in positive or double-negative dependent heterogeneity in cell cycle activity to double-negative feedback regulation, distinct cellular states within a population feedback regulation involving CDK2, p21, and E3 ubiquitin ligases. can arise (1, 14–18). Because of the role of p21 in the double- In support of this mechanism, analysis of cells at a point before cell negative feedback regulation of cell cycle activity, we hypothesized cycle entry (i.e., before the G1/S transition) revealed a p21–CDK2 axis that p21 controlled population heterogeneity in quiescent and that determines quiescent and cycling cell states.
    [Show full text]
  • Protein-Protein Interactions Among Signaling Pathways May Become New Therapeutic Targets in Liver Cancer (Review)
    ONCOLOGY REPORTS 35: 625-638, 2016 Protein-protein interactions among signaling pathways may become new therapeutic targets in liver cancer (Review) XIAO ZHANG1*, YULAN WANG1*, Jiayi WANG1,2 and FENYONG SUN1 1Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072; 2Translation Medicine of High Institute, Tongji University, Shanghai 200092, P.R. China Received May 29, 2015; Accepted July 6, 2015 DOI: 10.3892/or.2015.4464 Abstract. Numerous signaling pathways have been shown to be 1. Introduction dysregulated in liver cancer. In addition, some protein-protein interactions are prerequisite for the uncontrolled activation Liver cancer is the sixth most common cancer and the second or inhibition of these signaling pathways. For instance, in most common cause of cancer-associated mortality world- the PI3K/AKT signaling pathway, protein AKT binds with wide (1). Approximately 75% of all primary liver cancer types a number of proteins such as mTOR, FOXO1 and MDM2 to are hepatocellular carcinoma (HCC) that formed from liver play an oncogenic role in liver cancer. The aim of the present cells. Liver cancer can be formed from other structures in review was to focus on a series of important protein-protein the liver such as bile duct, blood vessels and immune cells. interactions that can serve as potential therapeutic targets Secondary liver cancer is a result of metastasis of cancer from in liver cancer among certain important pro-carcinogenic other body sites into the liver. The major cause of primary liver signaling pathways. The strategies of how to investigate and cancer is viral infection with either hepatitis C virus (HCV) analyze the protein-protein interactions are also included in or hepatitis B virus (HBV), which leads to massive inflamma- this review.
    [Show full text]
  • A Skp2 Autoinduction Loop and Restriction Point Control
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE JCB: REPORTprovided by PubMed Central A Skp2 autoinduction loop and restriction point control Yuval Yung,1 Janice L. Walker,1 James M. Roberts,2 and Richard K. Assoian1 1Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 2Fred Hutchinson Cancer Research Center, Seattle, WA 98109 e describe a self-amplifying feedback loop continuous serum stimulation. Skp2 knock down inhibits that autoinduces Skp2 during G1 phase S phase entry in nontransformed mouse embryonic fi bro- progression. This loop, which contains Skp2 blasts but not in human papilloma virus–E7 expressing Wkip1 itself, p27 (p27), cyclin E–cyclin dependent kinase 2, fi broblasts. We propose that the essential role for Skp2- and the retinoblastoma protein, is closed through a newly dependent degradation of p27 is in the formation of an identifi ed, conserved E2F site in the Skp2 promoter. Inter- autoinduction loop that selectively controls the transition ference with the loop, by knockin of a Skp2-resistant p27 to mitogen-independence, and that Skp2-dependent pro- mutant (p27T187A), delays passage through the restriction teolysis may be dispensable when pocket proteins are point but does not interfere with S phase entry under constitutively inactivated. Introduction Skp2 is the limiting component of the E3 ligase controlling mitogen-independent cell cycle progression, also called the the proteosomal degradation of p27kip1 (p27) in late G1/S restriction point. phase (Carrano et al., 1999; Tsvetkov et al., 1999). Skp2 can also stimulate p27 degradation and S phase entry in serum- Results and discussion deprived cells (Sutterluty et al., 1999).
    [Show full text]
  • Short Article CAND1 Binds to Unneddylated CUL1 and Regulates
    Molecular Cell, Vol. 10, 1519–1526, December, 2002, Copyright 2002 by Cell Press CAND1 Binds to Unneddylated CUL1 Short Article and Regulates the Formation of SCF Ubiquitin E3 Ligase Complex Jianyu Zheng,1 Xiaoming Yang,1 Despite the importance of cullins in controlling many Jennifer M. Harrell,1 Sophia Ryzhikov,1 essential biological processes, the mechanism that reg- Eun-Hee Shim,1 Karin Lykke-Andersen,2 ulates the cullin-containing ubiquitin E3 ligases remains Ning Wei,2 Hong Sun,1 Ryuji Kobayashi,3 unclear. In SCF, the F box proteins are short-lived pro- and Hui Zhang1,4 teins that undergo CUL1/SKP1-dependent degradation 1Department of Genetics (Wirbelauer et al., 2000; Zhou and Howley, 1998). Dele- Yale University School of Medicine tion of the F box region abolishes the binding of F box 333 Cedar Street proteins to SKP1 and CUL1, and consequently increases 2 Department of Molecular, Cellular, the stability of F box proteins. This substrate-indepen- and Developmental Biology dent proteolysis of F box proteins is likely the result of Yale University autoubiquitination by the ubiquitin E2 and E1 enzymes New Haven, Connecticut 06520 through a CUL1/SKP1-dependent mechanism. 3 Cold Spring Harbor Laboratory The carboxy-terminal ends of cullins are often covalently Cold Spring Harbor, New York 11724 modified by a ubiquitin-like protein, NEDD8/RUB1, and this modification appears to associate with active E3 li- gases (Hochstrasser, 2000). Like ubiquitin modification, Summary neddylation requires E1 (APP-BP1 and UBA3)-activating and E2 (UBC12)-conjugating enzymes (Hochstrasser, The SCF ubiquitin E3 ligase regulates ubiquitin-depen- 2000).
    [Show full text]
  • Phosphorylation by Mtorc1 Stablizes Skp2 and Regulates Its
    Geng et al. Molecular Cancer (2017) 16:83 DOI 10.1186/s12943-017-0649-0 RESEARCH Open Access Phosphorylation by mTORC1 stablizes Skp2 and regulates its oncogenic function in gastric cancer Qirong Geng1,2†, Jianjun Liu1,3†, Zhaohui Gong4†, Shangxiang Chen1,3†, Shuai Chen1, Xiaoxing Li1, Yue Lu1,2, Xiaofeng Zhu1, Hui-kuan Lin5 and Dazhi Xu1,3* Abstract Background: Both mTOR and Skp2 play critical roles in gastric cancer (GC) tumorigenesis. However, potential mechanisms for the association between these two proteins remains unidentified. Methods: The regulatory role for mTORC1 in Skp2 stability was tested using ubiquitination assay. The functions of p-Skp2 (phosphorylation of Skp2) were studied in vitro and in vivo. Expression of p-Skp2 and p-mTOR (phosphorylation of mTOR) were shown in GC lines and in 169 human primary GC tissues. Results: mTORC1 can directly interact with Skp2 and phosphorylated Skp2 at Ser64, which sequentially protect Skp2 from ubiquitination and degradation. Furthermore, the phospho-deficient p-Skp2 (S64) mutant significantly suppresses GC cell proliferation and tumorigenesis. The expression of p-Skp2 was associated with p-mTOR in GC cell lines and tissues. Interestingly, the combination of p-Skp2 and p-mTOR was a better predictor of survival than either factor alone. Conclusion: The mTORC1 function to regulate Skp2 by Ser64 phosphorylation may represent an oncogenic event in GC tumorigenesis. Moreover, our study also indicates that Skp2 Ser64 expression is a potential indicator in the treatment of GC patients using mTORC1 inhibitor. Keywords: mTORC1, Phosphorylation, Skp2, Gastric cancer Background of gastric cancer. For example, there is an increasing Gastric cancer (GC) is still an important public health interest in studying the role of the mammalian target of problem, with the third leading cause of cancer-related rapamycin (mTOR) in gastric cancer.
    [Show full text]
  • Skp2 in the Ubiquitin‐Proteasome System: a Comprehensive Review
    Received: 19 November 2019 | Revised: 26 March 2020 | Accepted: 27 April 2020 DOI: 10.1002/med.21675 REVIEW ARTICLE Skp2 in the ubiquitin‐proteasome system: A comprehensive review Moges Dessale Asmamaw | Ying Liu | Yi-Chao Zheng | Xiao‐Jing Shi | Hong‐Min Liu State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Abstract Advanced Drug Preparation Technologies, The ubiquitin‐proteasome system (UPS) is a complex Henan Key Laboratory of Drug Quality Control & Evaluation, School of Pharmaceutical process that regulates protein stability and activity by Sciences, Zhengzhou University, Ministry of the sequential actions of E1, E2 and E3 enzymes to in- Education of China, Zhengzhou, Henan, China fluence diverse aspects of eukaryotic cells. However, due Correspondence to the diversity of proteins in cells, substrate selection is Xiao‐Jing Shi and Hong‐Min Liu, State Key Laboratory of Esophageal Cancer Prevention & a highly critical part of the process. As a key player in Treatment; Key Laboratory of Advanced Drug UPS, E3 ubiquitin ligases recruit substrates for ubiquiti- Preparation Technologies, Ministry of Education of China; Henan Key Laboratory of Drug nation specifically. Among them, RING E3 ubiquitin li- Quality Control & Evaluation; School of gases which are the most abundant E3 ubiquitin ligases Pharmaceutical Sciences, Zhengzhou University, 450001 Zhengzhou, Henan, China. contribute to diverse cellular processes. The multisubunit Email: [email protected] (X‐JS) and cullin‐RING ligases (CRLs) are the largest family of RING [email protected] (H‐ML) E3 ubiquitin ligases with tremendous plasticity in sub- Funding information strate specificity and regulate a vast array of cellular National Key Research Program of Proteins, functions.
    [Show full text]
  • A Haploid Genetic Screen Identifies the G1/S Regulatory Machinery As a Determinant of Wee1 Inhibitor Sensitivity
    A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity Anne Margriet Heijinka, Vincent A. Blomenb, Xavier Bisteauc, Fabian Degenera, Felipe Yu Matsushitaa, Philipp Kaldisc,d, Floris Foijere, and Marcel A. T. M. van Vugta,1 aDepartment of Medical Oncology, University Medical Center Groningen, University of Groningen, 9723 GZ Groningen, The Netherlands; bDivision of Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; cInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research, Proteos#3-09, Singapore 138673, Republic of Singapore; dDepartment of Biochemistry, National University of Singapore, Singapore 117597, Republic of Singapore; and eEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands Edited by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved October 21, 2015 (received for review March 17, 2015) The Wee1 cell cycle checkpoint kinase prevents premature mitotic Wee1 kinase at tyrosine (Tyr)-15 to prevent unscheduled Cdk1 entry by inhibiting cyclin-dependent kinases. Chemical inhibitors activity (5, 6). Conversely, timely activation of Cdk1 depends on of Wee1 are currently being tested clinically as targeted anticancer Tyr-15 dephosphorylation by one of the Cdc25 phosphatases drugs. Wee1 inhibition is thought to be preferentially cytotoxic in (7–10). When DNA is damaged, the downstream DNA damage p53-defective cancer cells. However, TP53 mutant cancers do not response (DDR) kinases Chk1 and Chk2 inhibit Cdc25 phos- respond consistently to Wee1 inhibitor treatment, indicating the phatases through direct phosphorylation, which blocks Cdk1 existence of genetic determinants of Wee1 inhibitor sensitivity other activation (11–13).
    [Show full text]
  • Discriminative SKP2 Interactions with CDK-Cyclin Complexes Support a Cyclin A-Specific Role in P27kip1 Degradation
    Discriminative SKP2 Interactions with CDK- Cyclin Complexes Support a Cyclin A- Specific Role in p27KIP1 Degradation. Item Type Article Authors Salamina, Marco; Montefiore, Bailey C; Liu, Mengxi; Wood, Daniel J; Heath, Richard; Ault, James R; Wang, Lan-Zhen; Korolchuk, Svitlana; Baslé, Arnaud; Pastok, Martyna W; Reeks, Judith; Tatum, Natalie J; Sobott, Frank; Arold, Stefan T.; Pagano, Michele; Noble, Martin E M; Endicott, Jane A Citation Salamina, M., Montefiore, B. C., Liu, M., Wood, D. J., Heath, R., Ault, J. R., … Endicott, J. A. (2021). Discriminative SKP2 interactions with CDK-cyclin complexes support a cyclin A- specific role in p27KIP1 degradation. Journal of Molecular Biology, 166795. doi:10.1016/j.jmb.2020.166795 Eprint version Publisher's Version/PDF DOI 10.1016/j.jmb.2020.166795 Publisher Elsevier BV Journal Journal of molecular biology Rights This is an open access article under the CC BY license. Download date 29/09/2021 07:35:00 Item License http://creativecommons.org/licenses/by-nc-nd/4.0/ Link to Item http://hdl.handle.net/10754/667206 Research Article Discriminative SKP2 Interactions with CDK-Cyclin Complexes Support a Cyclin A-Specific Role in p27KIP1 Degradation Marco Salamina 1, Bailey C. Montefiore 1, Mengxi Liu 2, Daniel J. Wood 1, Richard Heath 1, James R. Ault 3, Lan-Zhen Wang 1, Svitlana Korolchuk 1, Arnaud Basle´ 4, Martyna W. Pastok 1, Judith Reeks 1, Natalie J. Tatum 1, ⇑ Frank Sobott 3, Stefan T. Arold 5,6, Michele Pagano 2, Martin E. M. Noble 1 and ⇑ Jane A. Endicott 1 1 - Newcastle University Centre for Cancer,
    [Show full text]
  • The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer
    International Journal of Molecular Sciences Review The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer 1,2, 1,2, 1,2, 1,2 1,2 Lei Ding y, Jiaqi Cao y, Wen Lin y, Hongjian Chen , Xianhui Xiong , Hongshun Ao 1,2, Min Yu 1,2, Jie Lin 1,2 and Qinghua Cui 1,2,* 1 Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; [email protected] (L.D.); [email protected] (J.C.); [email protected] (W.L.); [email protected] (H.C.); [email protected] (X.X.); [email protected] (H.A.); [email protected] (M.Y.); [email protected] (J.L.) 2 Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China * Correspondence: [email protected] The authors contributed equally to this work. y Received: 31 December 2019; Accepted: 24 February 2020; Published: 13 March 2020 Abstract: Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer.
    [Show full text]