{"doi":"10.18632/oncotarget.27508","title":"Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation","abstract":"// Asif Rashid 1 , 2 , Xin Duan 3 , Feng Gao 3 , Mengsu Yang 1 and Andrew Yen 2 1 Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, People’s Republic of China 2 Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA 3 The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China Correspondence to: Mengsu Yang, email: bhmyang@cityu.edu.hk Andrew Yen, email: ay13@cornell.edu Keywords: ATRA; roscovitine; APL; HL-60; Lyn Received: December 14, 2019     Accepted: February 08, 2020     Published: March 24, 2020 ABSTRACT Although ATRA represents a successful differentiation therapy for APL, it is largely ineffective for non-APL AMLs. Hence combination therapies using an agent targeting ATRA-regulated molecules that drive cell differentiation/arrest are of interest. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation/G0-arrest, we now observe that roscovitine enhanced nuclear enrichment of certain traditionally cytoplasmic signaling molecules and enhanced differentiation and cell cycle arrest. Roscovitine upregulated ATRA-induced nuclear c-Raf phosphorylation at S259 and S289/296/301. Nuclear c-Raf interacted with RB protein and specifically with pS608RB, the hinge region phosphorylation controlling E2F binding and cell cycle progression. ATRA-induced loss of pS608RB with cell cycle arrest was associated with loss of RB-sequestered c-Raf, thereby coupling cell cycle arrest and increased availability of c-Raf to promote differentiation. Part of this mechanism reflects promoting cell cycle arrest via ATRA-induced upregulation of the p27 Kip1 CDKI. Roscovitine also enhanced the ATRA-induced nuclear enrichment of other signaling molecules traditionally perceived as cytoplasmic promoters of proliferation, but now known to promote differentiation; in particular: SFKs, Lyn, Fgr; adaptor proteins, c-Cbl, SLP-76; a guanine exchange factor, Vav1; and a transcription factor, IRF-1. Akin to c-Raf, Lyn bound to RB, specifically to pS608RB. Lyn-pS608RB association was greatly diminished by ATRA and essentially lost in ATRA plus roscovitine treated cells. Interestingly Lyn-KD enhanced such ATRA-induced nuclear signaling and differentiation and made roscovitine more effective. ATRA thus mobilized traditionally cytoplasmic signaling molecules to the nucleus where they drove differentiation which were further enhanced by roscovitine.","journal":"Oncotarget","year":2020,"id":69009,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":366045,"name":"Xin Duan","orcid":"0009-0008-2931-8860","position":1,"is_corresponding":false},{"id":366046,"name":"Feng Gao","orcid":"0000-0002-0500-5527","position":2,"is_corresponding":false},{"id":366047,"name":"Mengsu Yang","orcid":"0000-0003-2083-2296","position":3,"is_corresponding":false},{"id":285677,"name":"Andrew Yen","orcid":"0000-0003-3456-0375","position":4,"is_corresponding":false},{"id":65862,"name":"Asif Rashid","orcid":"0000-0001-8463-7321","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-18T21:42:22.705573Z","pmid":"32256976","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}