Full Text Journal Articles by
Author Willem den Besten

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Prospecting for molecular glues.

Willem den Besten, J Russell Lipford,

Nat Chem Biol (Nature chemical biology)
[2020, 16(11):1157-1158]

Cited: 0 times

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PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network.

Kurt M Reichermeier, Ronny Straube, Justin M Reitsma, Michael J Sweredoski, Christopher M Rose, Annie Moradian, Willem den Besten, Trent Hinkle, Erik Verschueren, Georg Petzold, Nicolas H Thomä, Ingrid E Wertz, Raymond J Deshaies, Donald S Kirkpatrick,

Co-opting Cullin4 RING ubiquitin ligases (CRL4s) to inducibly degrade pathogenic proteins is emerging as a promising therapeutic strategy. Despite intense efforts to rationally design degrader molecules that co-opt CRL4s, much about the organization and regulation of these ligases remains elusive. Here, we establish protein interaction kinetics and estimation of stoichiometries ... Read more >>

Mol. Cell (Molecular cell)
[2020, 77(5):1092-1106.e9]

Cited: 0 times

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Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα).

Peter S Dragovich, Pragya Adhikari, Robert A Blake, Nicole Blaquiere, Jinhua Chen, Yun-Xing Cheng, Willem den Besten, Jinping Han, Steven J Hartman, Jintang He, Mingtao He, Ellen Rei Ingalla, Amrita V Kamath, Tracy Kleinheinz, Tommy Lai, Douglas D Leipold, Chun Sing Li, Qi Liu, Jiawei Lu, Ying Lu, Fanwei Meng, Lingyao Meng, Carl Ng, Kaishan Peng, Gail Lewis Phillips, Thomas H Pillow, Rebecca K Rowntree, Jack D Sadowsky, Deepak Sampath, Leanna Staben, Steven T Staben, John Wai, Kunpeng Wan, Xinxin Wang, BinQing Wei, Ingrid E Wertz, Jianfeng Xin, Keyang Xu, Hui Yao, Richard Zang, Donglu Zhang, Hao Zhou, Yongxin Zhao,

Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2020, 30(4):126907]

Cited: 2 times

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Conjugation of Indoles to Antibodies through a Novel Self-Immolating Linker.

Peter S Dragovich, Robert A Blake, Chunjiao Chen, Jinhua Chen, Josefa Chuh, Willem den Besten, Fang Fan, Aimee Fourie, Steven J Hartman, Changrong He, Jintang He, Ellen Rei Ingalla, Katherine R Kozak, Steven R Leong, Jiawei Lu, Yong Ma, Lingyao Meng, Michelle Nannini, Jason Oeh, Rachana Ohri, Gail Lewis Phillips, Thomas H Pillow, Rebecca K Rowntree, Deepak Sampath, Richard Vandlen, Breanna Vollmar, John Wai, Ingrid E Wertz, Keyang Xu, Zijin Xu, Donglu Zhang,

A novel strategy to attach indole-containing payloads to antibodies through a carbamate moiety and a self-immolating, disulfide-based linker is described. This new strategy was employed to connect a selective estrogen receptor down-regulator (SERD) to various antibodies in a site-selective manner. The resulting conjugates displayed potent, antigen-dependent down-regulation of estrogen receptor ... Read more >>

Chemistry (Chemistry (Weinheim an der Bergstrasse, Germany))
[2018, 24(19):4830-4834]

Cited: 1 time

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PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress.

Mei-Ling Kuo, Mabel Bin-Er Lee, Michelle Tang, Willem den Besten, Shuya Hu, Michael J Sweredoski, Sonja Hess, Chih-Ming Chou, Chun A Changou, Mingming Su, Wei Jia, Leila Su, Yun Yen,

Ribonucleotide reductase small subunit B (RRM2B) is a stress response protein that protects normal human fibroblasts from oxidative stress. However, the underlying mechanism that governs this function is not entirely understood. To identify factors that interact with RRM2B and mediate anti-oxidation function, large-scale purification of human Flag-tagged RRM2B complexes was ... Read more >>

Sci Rep (Scientific reports)
[2016, 6:18846]

Cited: 20 times

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p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition.

Senthil K Radhakrishnan, Willem den Besten, Raymond J Deshaies,

Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery (i.e., 'bounce-back') of proteasome activity. We previously demonstrated that the transcription factor Nrf1/NFE2L1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, ... Read more >>

Elife (eLife)
[2014, 3:e01856]

Cited: 79 times

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p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition

Senthil Radhakrishnan, Willem den Besten, Raymond Deshaies,

Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery (i.e. 'bounce-back') of proteasome activity. We previously demonstrated that the transcription factor Nrf1/NFE2L1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, ... Read more >>

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Cited: 0 times

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NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway.

Willem den Besten, Rati Verma, Gary Kleiger, Robert S Oania, Raymond J Deshaies,

The AAA+ ATPase p97 and its UBA-UBX cofactors are thought to extract ubiquitinated proteins from membranes or protein complexes as a prelude to their degradation. However, for many cofactors ubiquitinated targets have not yet been identified, leaving their biological function unclear. Previous analysis has linked the p97 pathway to cullin-RING ... Read more >>

Nat Struct Mol Biol (Nature structural & molecular biology)
[2012, 19(5):511-6, S1]

Cited: 45 times

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Differential post-transcriptional regulation of two Ink4 proteins, p18 Ink4c and p19 Ink4d.

Antoine Forget, Olivier Ayrault, Willem den Besten, Mei-Ling Kuo, Charles J Sherr, Martine F Roussel,

Cyclin(-D-)-dependent kinase (Cdk) inhibitors of the Ink4 family specifically bind to Cdk4 and Cdk6, but not to other Cdks. Ink4c and Ink4d mRNAs are maximally and periodically expressed during the G(2)/M phase of the cell division cycle, but the abundance of their encoded proteins is regulated through distinct mechanisms. Both ... Read more >>

Cell Cycle (Cell cycle (Georgetown, Tex.))
[2008, 7(23):3737-3746]

Cited: 9 times

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Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3.

Mei-Ling Kuo, Willem den Besten, Mary C Thomas, Charles J Sherr,

The stabilization and subcellular localization of the p19(Arf) tumor suppressor protein and the SUMO-2/3 deconjugating protease Senp3 each depend upon their binding to the abundant nucleolar protein nucleophosmin (Npm/B23). Senp3 and p19(Arf) antagonize each other's functions in regulating the SUMOylation of target proteins including Npm itself. The p19(Arf) protein triggers ... Read more >>

Cell Cycle (Cell cycle (Georgetown, Tex.))
[2008, 7(21):3378-3387]

Cited: 36 times

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Ubiquitination of, and sumoylation by, the Arf tumor suppressor.

Willem den Besten, Mei-Ling Kuo, Kenji Tago, Richard T Williams, Charles J Sherr,

The Ink4a-Arf locus, which encodes two distinct tumor suppressor proteins, is inactivated in many cancers. Whereas p16Ink4a is an inhibitor of cyclin D-dependent kinases, p19Arf (p14ARF in humans) antagonizes the E3 ubiquitin protein ligase activity of Mdm2 to activate p53. We now recognize that Arf functions in both p53-dependent and ... Read more >>

Isr. Med. Assoc. J. (The Israel Medical Association journal : IMAJ)
[2006, 8(4):249-251]

Cited: 10 times

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Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia.

Richard T Williams, Willem den Besten, Charles J Sherr,

Retroviral transduction of the BCR-ABL kinase into primary mouse bone marrow cells lacking the Arf tumor suppressor rapidly generates polyclonal populations of continuously self-renewing pre-B cells, virtually all of which have leukemic potential. Intravenous infusion of 20 such cells into healthy syngeneic mice induces rapidly fatal, transplantable lymphoblastic leukemias that ... Read more >>

Genes Dev. (Genes & development)
[2007, 21(18):2283-2287]

Cited: 104 times

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N-terminal polyubiquitination and degradation of the Arf tumor suppressor.

Mei-Ling Kuo, Willem den Besten, David Bertwistle, Martine F Roussel, Charles J Sherr,

Unknown mechanisms govern degradation of the p19Arf tumor suppressor, an activator of p53 and inhibitor of ribosomal RNA processing. Kinetic metabolic labeling of cells with [3H]-leucine indicated that p19Arf is a relatively stable protein (half-life approximately 6 h) whose degradation depends upon the ubiquitin-proteasome pathway. Although p19Arf binds to the ... Read more >>

Genes Dev. (Genes & development)
[2004, 18(15):1862-1874]

Cited: 117 times

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Myeloid leukemia-associated nucleophosmin mutants perturb p53-dependent and independent activities of the Arf tumor suppressor protein.

Willem den Besten, Mei-Ling Kuo, Richard T Williams, Charles J Sherr,

Nucleophosmin (NPM or B23) plays key roles in ribosome biogenesis, centrosome duplication, and maintenance of genomic integrity. Mutations affecting the carboxylterminal domain of NPM occur in a significant percentage of adult patients with acute myeloid leukemia (AML), and these alterations create an additional nuclear export signal that relocalizes much of ... Read more >>

Cell Cycle (Cell cycle (Georgetown, Tex.))
[2005, 4(11):1593-1598]

Cited: 51 times

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N-Terminal polyubiquitination of the ARF tumor suppressor, a natural lysine-less protein.

Mei-Ling Kuo, Willem den Besten, Charles J Sherr,

Ubiquitin-dependent proteolysis by proteasomes generally depends upon the conjugation of polyubiquitin chains to lysine epsilon-NH(2) groups within the targeted proteins. However, engineered lysine-less mutants of certain viral and cellular proteins can undergo polyubiquitination at their N-termini. Is N-terminal polyubiquitination a physiologic process, and how many cellular proteins can be targeted ... Read more >>

Cell Cycle (Cell cycle (Georgetown, Tex.))
[2004, 3(11):1367-1369]

Cited: 10 times

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Developmental regulation and downstream effects of the knox class homeobox genes Oskn2 and Oskn3 from rice.

A Dorien Postma-Haarsma, Saskia Rueb, Enrico Scarpella, Willem den Besten, J Harry C Hoge, Annemarie H Meijer,

Plant homeobox genes of the class 1 knox (knotted1-like) type are involved in the regulation of shoot apical meristem formation and function. Their expression generally occurs either throughout the meristem or specifically at the lateral organ boundaries. Down-regulation in the organ primordia is tightly controlled and misexpression in leaves leads ... Read more >>

Plant Mol. Biol. (Plant molecular biology)
[2002, 48(4):423-441]

Cited: 9 times

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Arf induces p53-dependent and -independent antiproliferative genes.

Mei-Ling Kuo, Eric J Duncavage, Rose Mathew, Willem den Besten, Deqing Pei, Deanna Naeve, Tadashi Yamamoto, Cheng Cheng, Charles J Sherr, Martine F Roussel,

The tumor suppressor p19(Arf) (p14(ARF) in humans), encoded by the Ink4a/Arf locus, is mutated, deleted, or silenced in many forms of cancer. p19(Arf) induces growth arrest by antagonizing the activity of the p53-negative regulator, Mdm2, thereby inducing a p53 transcriptional response. p19(Arf) can also inhibit cell cycle progression of mouse ... Read more >>

Cancer Res. (Cancer research)
[2003, 63(5):1046-1053]

Cited: 61 times

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Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18(Ink4c) and p19(Ink4d).

F Zindy, W den Besten, B Chen, J E Rehg, E Latres, M Barbacid, J W Pollard, C J Sherr, P E Cohen, M F Roussel,

Male mice lacking both the Ink4c and Ink4d genes, which encode two inhibitors of D-type cyclin-dependent kinases (Cdks), are infertile, whereas female fecundity is unaffected. Both p18(Ink4c) and p19(Ink4d) are expressed in the seminiferous tubules of postnatal wild-type mice, being largely confined to postmitotic spermatocytes undergoing meiosis. Their combined loss ... Read more >>

Mol. Cell. Biol. (Molecular and cellular biology)
[2001, 21(9):3244-3255]

Cited: 52 times

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