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      Post-translational modifications on the retinoblastoma protein

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          Abstract

          The retinoblastoma protein (pRb) functions as a cell cycle regulator controlling G1 to S phase transition and plays critical roles in tumour suppression. It is frequently inactivated in various tumours. The functions of pRb are tightly regulated, where post-translational modifications (PTMs) play crucial roles, including phosphorylation, ubiquitination, SUMOylation, acetylation and methylation. Most PTMs on pRb are reversible and can be detected in non-cancerous cells, playing an important role in cell cycle regulation, cell survival and differentiation. Conversely, altered PTMs on pRb can give rise to anomalies in cell proliferation and tumourigenesis. In this review, we first summarize recent findings pertinent to how individual PTMs impinge on pRb functions. As many of these PTMs on pRb were published as individual articles, we also provide insights on the coordination, either collaborations and/or competitions, of the same or different types of PTMs on pRb. Having a better understanding of how pRb is post-translationally modulated should pave the way for developing novel and specific therapeutic strategies to treat various human diseases.

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          Systematic and quantitative assessment of the ubiquitin-modified proteome.

          Despite the diverse biological pathways known to be regulated by ubiquitylation, global identification of substrates that are targeted for ubiquitylation has remained a challenge. To globally characterize the human ubiquitin-modified proteome (ubiquitinome), we utilized a monoclonal antibody that recognizes diglycine (diGly)-containing isopeptides following trypsin digestion. We identify ~19,000 diGly-modified lysine residues within ~5000 proteins. Using quantitative proteomics we monitored temporal changes in diGly site abundance in response to both proteasomal and translational inhibition, indicating both a dependence on ongoing translation to observe alterations in site abundance and distinct dynamics of individual modified lysines in response to proteasome inhibition. Further, we demonstrate that quantitative diGly proteomics can be utilized to identify substrates for cullin-RING ubiquitin ligases. Interrogation of the ubiquitinome allows for not only a quantitative assessment of alterations in protein homeostasis fidelity, but also identification of substrates for individual ubiquitin pathway enzymes. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Histone demethylation mediated by the nuclear amine oxidase homolog LSD1.

            Posttranslational modifications of histone N-terminal tails impact chromatin structure and gene transcription. While the extent of histone acetylation is determined by both acetyltransferases and deacetylases, it has been unclear whether histone methylation is also regulated by enzymes with opposing activities. Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. Lysine demethylation occurs via an oxidation reaction that generates formaldehyde. Importantly, RNAi inhibition of LSD1 causes an increase in H3 lysine 4 methylation and concomitant derepression of target genes, suggesting that LSD1 represses transcription via histone demethylation. The results thus identify a histone demethylase conserved from S. pombe to human and reveal dynamic regulation of histone methylation by both histone methylases and demethylases.
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              RB and cell cycle progression.

              The Rb protein is a tumor suppressor, which plays a pivotal role in the negative control of the cell cycle and in tumor progression. It has been shown that Rb protein (pRb) is responsible for a major G1 checkpoint, blocking S-phase entry and cell growth. The retinoblastoma family includes three members, Rb/p105, p107 and Rb2/p130, collectively referred to as 'pocket proteins'. The pRb protein represses gene transcription, required for transition from G1 to S phase, by directly binding to the transactivation domain of E2F and by binding to the promoter of these genes as a complex with E2F. pRb represses transcription also by remodeling chromatin structure through interaction with proteins such as hBRM, BRG1, HDAC1 and SUV39H1, which are involved in nucleosome remodeling, histone acetylation/deacetylation and methylation, respectively. Loss of pRb functions may induce cell cycle deregulation and so lead to a malignant phenotype. Gene inactivation of pRB through chromosomal mutations is one of the principal reasons for retinoblastoma tumor development. Functional inactivation of pRb by viral oncoprotein binding is also shown in many neoplasias such as cervical cancer, mesothelioma and AIDS-related Burkitt's lymphoma.
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                Author and article information

                Contributors
                waikit@cuhk.edu.hk
                Journal
                J Biomed Sci
                J Biomed Sci
                Journal of Biomedical Science
                BioMed Central (London )
                1021-7770
                1423-0127
                1 June 2022
                1 June 2022
                2022
                : 29
                : 33
                Affiliations
                [1 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Ophthalmology & Visual Sciences, , The Chinese University of Hong Kong, ; Hong Kong, China
                [2 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Hong Kong Hub of Paediatric Excellence, , The Chinese University of Hong Kong, ; Hong Kong, China
                [3 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Ophthalmology & Visual Sciences, , The Chinese University of Hong Kong, Hong Kong Eye Hospital, ; 147K Argyle Street, Kowloon, Hong Kong China
                Author information
                http://orcid.org/0000-0003-2903-3247
                Article
                818
                10.1186/s12929-022-00818-x
                9161509
                35650644
                484a3e99-38e8-4172-8de9-0b759d23598b
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 30 January 2022
                : 26 May 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100005847, Health and Medical Research Fund;
                Award ID: 07180306
                Award ID: PR-HKCH-8
                Award ID: 06170896
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                Molecular medicine
                retinoblastoma,phosphorylation,ubiquitination,sumoylation,acetylation,methylation
                Molecular medicine
                retinoblastoma, phosphorylation, ubiquitination, sumoylation, acetylation, methylation

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