Review

Authors: Hani Rayess, Marilene B Wang, Eri S Srivatsan...

Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16-mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex (1) and PRC2 (Pombe repressor complex (2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression, transcription factors CTCF, Sp1 and Ets family members activate p16 transcription. Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16.

Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Gene Expression; Humans; Neoplasms; Retinoblastoma Protein; Telomere Shortening; Tumor Suppressor Protein p53

PubMed: 22025288
DOI: 10.1002/ijc.27316

Authors: Evgeny Zatulovskiy, Shuyuan Zhang, Daniel F Berenson...

Cell size is fundamental to cell physiology. For example, cell size determines the spatial scale of organelles and intracellular transport and thereby affects biosynthesis. Although some genes that affect mammalian cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive. We show that cell growth during the G phase of the cell division cycle dilutes the cell cycle inhibitor Retinoblastoma protein (Rb) to trigger division in human cells. overexpression increased cell size and G duration, whereas deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of the G phase. Thus, Rb dilution through cell growth in G provides one of the long-sought molecular mechanisms that promotes cell size homeostasis.

Topics: Cell Cycle Checkpoints; Cell Division; Cell Proliferation; Cell Size; G1 Phase; Humans; Retinoblastoma Protein

PubMed: 32703881
DOI: 10.1126/science.aaz6213

Authors: Ezgi Dicle Serbes, Nanda Horeweg, Carlos Parra-Herran...

Of the 4 molecular subtypes of endometrial cancer (EC), p53-abnormal (p53abn) EC is associated with abundant copy number alterations and the worst clinical outcome. Patients with p53abn EC have the highest risk of disease recurrence and death, independent of tumor grade and histologic subtype. Currently, all invasive p53abn ECs are considered high risk, and no prognostic biomarkers have yet been found that can aid in clinical management. Here, we aimed to test whether loss of retinoblastoma (RB) protein expression using immunohistochemistry has the potential for prognostic refinement of p53abn EC. A large cohort of 227 p53abn ECs collected from the PORTEC-1/2/3 clinical trials and the Medisch Spectrum Twente cohort study was investigated, and RB loss was identified in 7.0% (n = 16/227). RB-lost p53abn ECs were predominantly high-grade endometrioid ECs (n = 6, 37.5%) and carcinosarcomas with endometrioid-type epithelial component (n = 5, 31.3%). Histologically, RB-lost p53abn ECs were typified by high-grade nuclear atypia (n = 16, 100%), predominantly solid growth pattern (n = 15/16, 93.8%), and polypoid growth (n = 9/16, 56.3%). Copy number loss involving the RB1 locus was identified in the majority of RB-lost p53abn EC (n = 13/14, 92.9%), explaining the loss of RB expression. Comparative analysis also showed that RB-lost p53abn ECs were diagnosed at earlier stages than RB-retained p53abn EC (P = .014). Interestingly, RB-lost p53abn EC showed prolonged time to overall recurrence (P = .038), even within stage I alone (P = .040). These findings highlight distinct morphomolecular features in RB-lost p53abn ECs and confirm the utility of RB immunohistochemistry as a surrogate for underlying molecular RB1 alterations. To our knowledge, this is the first study to show the potential use of RB in prognostic refinement of p53abn EC, although validation is warranted.

Topics: Humans; Female; Endometrial Neoplasms; Retinoblastoma Protein; Tumor Suppressor Protein p53; Middle Aged; Biomarkers, Tumor; Aged; Immunohistochemistry; Adult; Carcinoma, Endometrioid; Prognosis; Aged, 80 and over; Carcinosarcoma; Ubiquitin-Protein Ligases; Retinoblastoma Binding Proteins

PubMed: 39577664
DOI: 10.1016/j.modpat.2024.100660

Review

Authors: Linbin Zhou, Danny Siu-Chun Ng, Jason C Yam...

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.

Topics: Acetylation; Humans; Phosphorylation; Protein Processing, Post-Translational; Retinoblastoma Protein; Ubiquitination

PubMed: 35650644
DOI: 10.1186/s12929-022-00818-x

Review

Authors: Yiwen Wang, Rui Yang, Rui Liu...

The treatment of multiple myeloma (MM) has significantly advanced; however, the underlying genetic mechanisms remain elusive. Clonal events and genetic alterations are recognized as pivotal in the pathogenesis of MM. It is now understood that a multitude of gene mutations, including those affecting RAS, , , and 1q21 amplification, are prevalent in this disease. The incorporation of several high-risk genetic factors into the Second Revision of the International Staging System (R-ISS) underscores the prognostic significance of genetic aberrations in MM. The retinoblastoma gene (), located in 13q14, encodes the retinoblastoma protein (pRB), a tumor suppressor that regulates cell cycle progression. Deletion of , which is a frequent event in MM, contributes to tumorigenesis by disrupting cell cycle control. In this respect, loss has been implicated in the progression of MM through its influence on interleukin-6 (IL-6) secretion and cell proliferation. This review comprehensively summarizes the role of in MM and expounds on the potential of targeting as a therapeutic strategy for this malignancy.

Topics: Humans; Multiple Myeloma; Retinoblastoma Binding Proteins; Animals; Retinoblastoma Protein; Mutation; Ubiquitin-Protein Ligases

PubMed: 39664374
DOI: 10.3389/fimmu.2024.1415972

Authors: Laura D Attardi, Julien Sage

The retinoblastoma tumor suppressor RB is well known for its capacity to restrict cell cycle progression at the G1/S transition of the cell cycle by controlling the transcription of cell cycle genes. In this issue of Genes & Development, Hilgendorf and colleagues (pp. 1003-1015) have identified a novel tumor suppressor function for RB independent of its role as a transcriptional regulator, in which RB directly activates the apoptosis regulator Bax at the mitochondria to promote cell death.

Topics: Animals; Apoptosis; Gene Expression Regulation, Neoplastic; Humans; Mitochondria; Retinoblastoma Protein

PubMed: 23651852
DOI: 10.1101/gad.219451.113

Authors: Sivasankar Putta, Lucia Alvarez, Stephan Lüdtke...

The retinoblastoma protein (Rb) and its homologs p107 and p130 are critical regulators of gene expression during the cell cycle and are commonly inactivated in cancer. Rb proteins use their "pocket domain" to bind an LxCxE sequence motif in other proteins, many of which function with Rb proteins to co-regulate transcription. Here, we present binding data and crystal structures of the p107 pocket domain in complex with LxCxE peptides from the transcriptional co-repressor proteins HDAC1, ARID4A, and EID1. Our results explain why Rb and p107 have weaker affinity for cellular LxCxE proteins compared with the E7 protein from human papillomavirus, which has been used as the primary model for understanding LxCxE motif interactions. Our structural and mutagenesis data also identify and explain differences in Rb and p107 affinities for some LxCxE-containing sequences. Our study provides new insights into how Rb proteins bind their cell partners with varying affinity and specificity.

Topics: Cell Cycle; Humans; Repressor Proteins; Retinoblastoma Protein; Retinoblastoma-Like Protein p130

PubMed: 35716663
DOI: 10.1016/j.str.2022.05.019

Authors: Bojana Jovanović, Sarah E Church, Kara M Gorman...

PURPOSE

Triple-negative breast cancer (TNBC) is a heterogeneous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted toward tumors carrying a specific genomic, transcriptomic, or protein biomarker, it is poorly understood how these biomarkers are correlated.

EXPERIMENTAL DESIGN

To better understand the molecular features of TNBC and their correlation with one another, we performed multimodal profiling on a cohort of 95 TNBC. Our approach involved quantifying tumor-infiltrating lymphocytes through hematoxylin and eosin staining, assessing the abundance of retinoblastoma, androgen receptor, and PDL1 proteins through IHC, and carrying out transcriptomic profiling using the NanoString BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival.

RESULTS

Levels of RB1 mRNA and RB proteins are better correlated with markers of retinoblastoma functionality than RB1 mutational status. Luminal androgen receptor tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PDL1-positive by the presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared with HER2-zero. The majority of TNBC were classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival.

CONCLUSIONS

Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.

Topics: Humans; Triple Negative Breast Neoplasms; Female; Biomarkers, Tumor; Gene Expression Profiling; Receptors, Androgen; Retinoblastoma Binding Proteins; Lymphocytes, Tumor-Infiltrating; B7-H1 Antigen; Middle Aged; Retinoblastoma Protein; Prognosis; Transcriptome; Mutation; Gene Expression Regulation, Neoplastic; Aged; Adult; Ubiquitin-Protein Ligases

PubMed: 39136550
DOI: 10.1158/1078-0432.CCR-23-1242

Authors: Erica M Walsh, MengMeng Niu, Johann Bergholz...

The p53 tumor suppressor gene plays a critical role in regulation of proliferation, cell death and differentiation. The MDM2 oncoprotein is a major negative regulator for p53 by binding to and targeting p53 for proteasome-mediated degradation. The small molecule inhibitor, nutlin-3, disrupts MDM2-p53 interaction resulting in stabilization and activation of p53 protein. We have previously shown that nutlin-3 activates p53, leading to MDM2 accumulation as concomitant of reduced retinoblastoma (Rb) protein stability. It is well known that Rb is important in muscle development and myoblast differentiation and that rhabdomyosarcoma (RMS), or cancer of the skeletal muscle, typically harbors MDM2 amplification. In this study, we show that nutlin-3 inhibited myoblast proliferation and effectively prevented myoblast differentiation, as evidenced by lack of expression of muscle differentiation markers including myogenin and myosin heavy chain (MyHC), as well as a failure to form multinucleated myotubes, which were associated with dramatic increases in MDM2 expression and decrease in Rb protein levels. These results indicate that nutlin-3 can effectively inhibit muscle cell differentiation.

Topics: Animals; Cell Differentiation; Cell Line; Cell Proliferation; Down-Regulation; Imidazoles; Mice; Muscle Development; Myoblasts; Piperazines; Proto-Oncogene Proteins c-mdm2; Retinoblastoma Protein

PubMed: 25871794
DOI: 10.1016/j.bbrc.2015.04.024

Authors: Tyler J Liban, Edgar M Medina, Sarvind Tripathi...

The retinoblastoma protein (Rb) and the homologous pocket proteins p107 and p130 negatively regulate cell proliferation by binding and inhibiting members of the E2F transcription factor family. The structural features that distinguish Rb from other pocket proteins have been unclear but are critical for understanding their functional diversity and determining why Rb has unique tumor suppressor activities. We describe here important differences in how the Rb and p107 C-terminal domains (CTDs) associate with the coiled-coil and marked-box domains (CMs) of E2Fs. We find that although CTD-CM binding is conserved across protein families, Rb and p107 CTDs show clear preferences for different E2Fs. A crystal structure of the p107 CTD bound to E2F5 and its dimer partner DP1 reveals the molecular basis for pocket protein-E2F binding specificity and how cyclin-dependent kinases differentially regulate pocket proteins through CTD phosphorylation. Our structural and biochemical data together with phylogenetic analyses of Rb and E2F proteins support the conclusion that Rb evolved specific structural motifs that confer its unique capacity to bind with high affinity those E2Fs that are the most potent activators of the cell cycle.

Topics: Crystallography, X-Ray; E2F Transcription Factors; Humans; Protein Domains; Retinoblastoma Protein; Retinoblastoma-Like Protein p107

PubMed: 28439018
DOI: 10.1073/pnas.1619170114