Role of the retinoblastoma protein in the pathogenesis of human cancer.

The retinoblastoma gene (RB-1) was originally identified as the gene involved in hereditary retinoblastoma. However, RB-1 mutations are found in a number of common mesenchymal and epithelial malignancies. The retinoblastoma protein (pRB) acts as a transcriptional regulator of genes involved in DNA synthesis and cell-cycle control. In this regard, the functional interaction between pRB and the E2F transcription factor family appears to be critical. The pRB-E2F interaction is, in turn, regulated by a pathway that includes cyclin D1, cdk4, and p16. Mutations that affect this pathway have been documented in nearly every type of adult cancer. Thus, perturbation of pRB function may be required for the development of cancer. Insights into the biochemical functions of pRB, and its upstream regulators, may form the basis for the development of novel antineoplastic agents.

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The Role of the E2F Transcription Factor Family in UV-Induced Apoptosis

International Journal of Molecular Sciences ◽

10.3390/ijms12128947 ◽

2011 ◽

Vol 12 (12) ◽

pp. 8947-8960 ◽

Cited By ~ 13

Author(s):

Mehlika Hazar-Rethinam ◽

Liliana Endo-Munoz ◽

Orla Gannon ◽

Nicholas Saunders

Keyword(s):

Transcription Factor ◽

Transcription Factor Family ◽

E2f Transcription Factor ◽

Induced Apoptosis

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Homeobox genes and Hepatocellular Carcinoma

10.20944/preprints201904.0224.v1 ◽

2019 ◽

Author(s):

Kwei-Yan Liu ◽

Li-Ting Wang ◽

Shih-Hsien Hsu ◽

Shen-Nien Wang

Keyword(s):

Hepatocellular Carcinoma ◽

Hox Genes ◽

Viral Infections ◽

Human Cancer ◽

Control Cell ◽

Environmental Toxins ◽

Regulatory Mechanisms ◽

Transcription Factor Family ◽

Potential Use

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer, and is the third leading cause of cancer-related deaths each year. It involves a multi-step progression and is strongly associated with chronic inflammation induced by the intake of environmental toxins and/or viral infections (i.e., hepatitis B and C viruses). Although several genetic dysregulations are considered to be involved in disease progression, the detailed regulatory mechanisms are not well defined. Homeobox (Hox) genes that encode transcription factors with homeodomains control cell growth, differentiation, and morphogenesis in embryonic development. Recently, more aberrant expressions of Hox genes were found in a wide variety of human cancer, including HCC. In this review, we summarize the currently available evidence related to the role of Hox genes in the development of HCC. The objective is to determine the roles of this conserved transcription factor family and its potential use as a therapeutic target in future investigations.

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Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1619170114 ◽

2017 ◽

Vol 114 (19) ◽

pp. 4942-4947 ◽

Cited By ~ 12

Author(s):

Tyler J. Liban ◽

Edgar M. Medina ◽

Sarvind Tripathi ◽

Satyaki Sengupta ◽

R. William Henry ◽

...

Keyword(s):

Phylogenetic Analyses ◽

Coiled Coil ◽

Retinoblastoma Protein ◽

Structural Features ◽

Transcription Factor Family ◽

Pocket Proteins ◽

Cyclin Dependent Kinases ◽

Pocket Protein ◽

E2f Transcription Factor ◽

E2f Proteins

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.

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Role of the retinoblastoma gene in the initiation and progression of human cancer.

Journal of Clinical Investigation ◽

10.1172/jci114575 ◽

1990 ◽

Vol 85 (4) ◽

pp. 988-993 ◽

Cited By ~ 100

Author(s):

W F Benedict ◽

H J Xu ◽

S X Hu ◽

R Takahashi

Keyword(s):

Human Cancer ◽

Retinoblastoma Gene

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Transcriptional inhibition by the retinoblastoma protein

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1993.0075 ◽

1993 ◽

Vol 340 (1293) ◽

pp. 333-336 ◽

Cited By ~ 6

Keyword(s):

Cell Cycle ◽

Transcription Factor ◽

Retinoblastoma Protein ◽

Specific Cell ◽

Retinoblastoma Gene ◽

Transcriptional Inhibition ◽

Human Tumours ◽

E2f Transcription Factor ◽

Cycle Dependent ◽

Regulation Of Cell Cycle

The retinoblastoma protein, pRB, appears to play a key role in coordinating the regulation of cell cycle position and transcriptional events. pRB undergoes specific cell-cycle-dependent phosphorylation, being underphosphorylated in G1 and heavily phosphorylated in S, G2, and M. The underphosphorylated form is able to interact with the E2F transcription factor. Recently, we have cloned a cDNA for E2F-1. By using this clone and a series of non-pRB binding mutants, we have been able to show that the binding of pRB to E2F-1 causes inhibition of E2F-mediated transactivation. pRB ’s inhibition of E2F-mediated transcription would be lost by mutation in the retinoblastoma gene in human tumours, by pRB s interaction with DNA tumour virus oncoproteins, or by phosphorylation during the cell cycle.

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Homeobox Genes and Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers11050621 ◽

2019 ◽

Vol 11 (5) ◽

pp. 621 ◽

Cited By ~ 1

Author(s):

Kwei-Yan Liu ◽

Li-Ting Wang ◽

Shih-Hsien Hsu ◽

Shen-Nien Wang

Keyword(s):

Hepatocellular Carcinoma ◽

Viral Infections ◽

Human Cancer ◽

Control Cell ◽

Homeobox Genes ◽

Environmental Toxins ◽

Regulatory Mechanisms ◽

Transcription Factor Family ◽

Potential Use

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, and is the third leading cause of cancer-related deaths each year. It involves a multi-step progression and is strongly associated with chronic inflammation induced by the intake of environmental toxins and/or viral infections (i.e., hepatitis B and C viruses). Although several genetic dysregulations are considered to be involved in disease progression, the detailed regulatory mechanisms are not well defined. Homeobox genes that encode transcription factors with homeodomains control cell growth, differentiation, and morphogenesis in embryonic development. Recently, more aberrant expressions of Homeobox genes were found in a wide variety of human cancer, including HCC. In this review, we summarize the currently available evidence related to the role of Homeobox genes in the development of HCC. The objective is to determine the roles of this conserved transcription factor family and its potential use as a therapeutic target in future investigations.

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ACE2/Angiotensin-(1-7)/Mas Receptor Axis in Human Cancer: Potential Role for Pediatric Tumors

Current Drug Targets ◽

10.2174/1389450121666200210124217 ◽

2020 ◽

Vol 21 (9) ◽

pp. 892-901 ◽

Cited By ~ 4

Author(s):

Ana Luiza Ataide Carneiro de Paula Gonzaga ◽

Vitória Andrade Palmeira ◽

Thomas Felipe Silva Ribeiro ◽

Larissa Braga Costa ◽

Karla Emília de Sá Rodrigues ◽

...

Keyword(s):

Clinical Trials ◽

Angiotensin Ii ◽

Pediatric Cancer ◽

Pediatric Patients ◽

Human Cancer ◽

Experimental Studies ◽

At1 Receptor ◽

Pediatric Tumors ◽

Mas Receptor

Background: Pediatric tumors remain the highest cause of death in developed countries. Research on novel therapeutic strategies with lesser side effects is of utmost importance. In this scenario, the role of Renin-Angiotensin System (RAS) axes, the classical one formed by angiotensinconverting enzyme (ACE), Angiotensin II and AT1 receptor and the alternative axis composed by ACE2, Angiotensin-(1-7) and Mas receptor, have been investigated in cancer. Objective: This review aimed to summarize the pathophysiological role of RAS in cancer, evidence for anti-tumor effects of ACE2/Angiotensin-(1-7)/Mas receptor axis and future therapeutic perspectives for pediatric cancer. Methods: Pubmed, Scopus and Scielo were searched in regard to RAS molecules in human cancer and pediatric patients. The search terms were “RAS”, “ACE”, “Angiotensin-(1-7)”, “ACE2”, “Angiotensin II”, “AT1 receptor”, “Mas receptor”, “Pediatric”, “Cancer”. Results: Experimental studies have shown that Angiotensin-(1-7) inhibits the growth of tumor cells and reduces local inflammation and angiogenesis in several types of cancer. Clinical trials with Angiotensin-( 1-7) or TXA127, a pharmaceutical grade formulation of the naturally occurring peptide, have reported promising findings, but not enough to recommend medical use in human cancer. In regard to pediatric cancer, only three articles that marginally investigated RAS components were found and none of them evaluated molecules of the alternative RAS axis. Conclusion: Despite the potential applicability of Angiotensin-(1-7) in pediatric tumors, the role of this molecule was never tested. Further clinical trials are necessary, also including pediatric patients, to confirm safety and efficiency and to define therapeutic targets.

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The Role of Sensing Peptides in the Cross-talk between Microbiota and Human Cancer Cells

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557518666180713112119 ◽

2018 ◽

Vol 18 (18) ◽

pp. 1567-1571

Author(s):

Anna Lucia Tornesello ◽

Luigi Buonaguro ◽

Maria Lina Tornesello ◽

Franco M. Buonaguro

Keyword(s):

Cancer Cells ◽

Cross Talk ◽

Human Cancer ◽

Human Cancer Cells ◽

The Cross

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The Role of Retinoblastoma Protein in Cell Cycle Regulation: An Updated Review

Current Molecular Medicine ◽

10.2174/1566524020666210104113003 ◽

2021 ◽

Vol 20 ◽

Author(s):

Rabih Roufayel ◽

Rabih Mezher ◽

Kenneth B. Storey

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Transcription Factors ◽

Cell Cycle Control ◽

Expression Of Genes ◽

E2f Transcription Factor ◽

Cellular Energetics ◽

Development And Differentiation ◽

E2f Transcription Factors ◽

Rb Phosphorylation

: Selected transcription factors have critical roles to play in organism survival by regulating the expression of genes that control the adaptations needed to handle stress conditions. The retinoblastoma (Rb) protein coupled with the E2F transcription factor family was demonstrated to have roles in controlling the cell cycle during freezing and associated environmental stresses (anoxia, dehydration). Rb phosphorylation or acetylation at different sites provide a mechanism for repressing cell proliferation that is under the control of E2F transcription factors in animals facing stresses that disrupt cellular energetics or cell volume controls. Other central regulators of the cell cycle including Cyclins, Cyclin dependent kinases (Cdks), and checkpoint proteins detect DNA damage or any improper replication, blocking further progression of cell cycle and interrupting cell proliferation. This review provides an insight into the molecular regulatory mechanisms of cell cycle control, focusing on Rb-E2F along with Cyclin-Cdk complexes typically involved in development and differentiation that need to be regulated in order to survive extreme cellular stress.

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