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Multiple Roles of the RB Family of Tumor Suppressors and...
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Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 27650

Special Issue Editors

Dr. Paola Indovina

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Guest Editor
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Interests: cell cycle; targeted therapy; RB family; tumor suppressors; SRC family kinases; WEE1 kinase; mesothelioma
Dr. Francesca Pentimalli

E-Mail Website
Guest Editor
Department of Medicine and Surgery, LUM University "Giuseppe DeGennaro", 70010 Casamassima, Italy
Interests: cell cycle; mesothelioma; DNA damage; tumor suppressor genes; RB family; p53; oncolytic viruses; cell death; CDK inhibitors; p27
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Antonio Giordano

E-Mail Website
Guest Editor
1. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
2. Department of Medical Biotechnologies, University of Siena, Siena, Italy
Interests: cell cycle; tumor suppressor genes; RB family; CDK inhibitors; environment and cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The RB1 protein—the first tumor suppressor—was discovered in the 1980s and, since then, its pathway has been found to be inactivated in most cancers. According to the canonical model, the tumor-suppressive activity of RB1 depends on its ability to restrain cell proliferation. However, evidence has shown RB1’s mode of action to be much more complex, with this factor undergoing different post-translational modifications and multiple protein interactions, whereby it controls a multitude of functions. These functions include DNA repair, preservation of chromosomal stability, cell death, senescence, immune response, metabolism, epithelial–mesenchymal transition, angiogenesis, stemness, cell lineage identity, and differentiation, the deregulation of which underlies both cancer onset and progression and impacts on the response to anticancer treatments. Thus, RB1 has emerged as an appealing therapeutic target and candidate to support therapeutic decisions.

However, the complexity of RB1’s functions, which remain controversial and underexplored in various contexts, and the difficulties in evaluating RB1’s functional status hinder the clinical translation of approaches aimed at exploiting the predictive, prognostic, and therapeutic value of this tumor suppressor. Moreover, RB1 belongs to a family of proteins, including RBL1/p107 and RBL2/p130, that have both overlapping and distinct functions. Although the key role of these other two RB family members (especially that of RBL2/p130) in cell-cycle exit events is well-recognized, there are much less data on the mechanisms of action of these proteins. This Special Issue will cover all of the aspects of the biology of RB proteins, with a particular focus on their emerging non-canonical functions and their involvement in the response to conventional treatments, targeted therapies, and immunotherapeutic approaches. Moreover, possible strategies exploiting RB family members therapeutically will be discussed. We hope that this Special Issue will help us to better understand the role of these crucial proteins in the neoplastic process and in cancer therapy and will point to new directions to tackle clinical translational hurdles. 

Dr. Paola Indovina
Dr. Francesca Pentimalli
Prof. Antonio Giordano
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • RB1
  • RBL2/p130
  • RBL1/p107
  • cancer therapy
  • predictive role
  • cell death
  • senescence
  • cell lineage identity
  • DNA repair
  • immune function

Published Papers (7 papers)

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Research

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17 pages, 2002 KiB  
Article
RBL1/p107 Expression Levels Are Modulated by Multiple Signaling Pathways
by Elisa Ventura, Carmelina Antonella Iannuzzi, Francesca Pentimalli, Antonio Giordano and Andrea Morrione
Cancers 2021, 13(19), 5025; https://doi.org/10.3390/cancers13195025 - 08 Oct 2021
Cited by 5 | Viewed by 2588
Abstract
The members of the retinoblastoma (RB) protein family, RB1/p105, retinoblastoma-like (RBL)1/p107 and RBL2/p130 are critical modulators of the cell cycle and their dysregulation has been associated with tumor initiation and progression. The activity of RB proteins is regulated by numerous pathways including oncogenic [...] Read more.
The members of the retinoblastoma (RB) protein family, RB1/p105, retinoblastoma-like (RBL)1/p107 and RBL2/p130 are critical modulators of the cell cycle and their dysregulation has been associated with tumor initiation and progression. The activity of RB proteins is regulated by numerous pathways including oncogenic signaling, but the molecular mechanisms of these functional interactions are not fully defined. We previously demonstrated that RBL2/p130 is a direct target of AKT and it is a key mediator of the apoptotic process induced by AKT inhibition. Here we demonstrated that RBL1/p107 levels are only minorly modulated by the AKT signaling pathway. In contrast, we discovered that RBL1/p107 levels are regulated by multiple pathways linked directly or indirectly to Ca2+-dependent signaling. Inhibition of the multifunctional calcium/calmodulin-dependent kinases (CaMKs) significantly reduced RBL1/p107 expression levels and phosphorylation, increased RBL1/p107 nuclear localization and led to cell cycle arrest in G0/G1. Targeting the Ca2+-dependent endopeptidase calpain stabilized RBL1/p107 levels and counteracted the reduction of RBL1/p107 levels associated with CaMKs inhibition. Thus, these novel observations suggest a complex regulation of RBL1/p107 expression involving different components of signaling pathways controlled by Ca2+ levels, including CaMKs and calpain, pointing out a significant difference with the mechanisms modulating the close family member RBL2/p130. Full article
(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)
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14 pages, 3338 KiB  
Article
Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
by Eva Moreno, Shusil K. Pandit, Mathilda J. M. Toussaint, Laura Bongiovanni, Liesbeth Harkema, Saskia C. van Essen, Elsbeth A. van Liere, Bart Westendorp and Alain de Bruin
Cancers 2021, 13(9), 2033; https://doi.org/10.3390/cancers13092033 - 23 Apr 2021
Cited by 6 | Viewed by 2503
Abstract
E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated [...] Read more.
E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and −8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently, it is unknown if and how RB and atypical E2Fs functionally interact in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life-spans compared to E2f7/8 or Rb deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. In contrast, loss of either E2f7 or E2f8 largely prevented the formation of pituitary tumors in Rb+/− mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of E2f7 or E2f8 in mice. E2F7 and −8 overexpression increased the incidence of tumors in the lungs, but not in other tissues. Collectively, these data show that atypical E2Fs can promote but also inhibit tumorigenesis depending on tissue type and RB status. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency. Full article
(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)
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12 pages, 6004 KiB  
Article
Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells
by Claire D. James, Siddharth Saini, Fatmata Sesay, Kevin Ko, Jessica Felthousen-Rusbasan, Audra N. Iness, Tara Nulton, Brad Windle, Mikhail G. Dozmorov, Iain M. Morgan and Larisa Litovchick
Cancers 2021, 13(3), 489; https://doi.org/10.3390/cancers13030489 - 27 Jan 2021
Cited by 6 | Viewed by 2969
Abstract
High-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 [...] Read more.
High-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 uses a LxCxE motif to bind RB proteins, impairing their ability to control cell-cycle dependent transcription. E7 disrupts DREAM (Dimerization partner, RB-like, E2F and MuvB), a transcriptional repressor complex that can include p130 or p107, but not pRb, which regulates genes required for cell cycle progression. However, it is not known whether disruption of DREAM plays a significant role in HPV-driven tumorigenesis. In the DREAM complex, LIN52 is an adaptor that binds directly to p130 via an E7-like LxSxE motif. Replacement of the LxSxE sequence in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, inhibiting proliferation. Our findings demonstrate that disruption of the DREAM complex by E7 is an important process promoting cellular proliferation by HR-HPV. Restoration of the DREAM complex in HR-HPV positive cells may therefore have therapeutic benefits in HR-HPV positive cancers. Full article
(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)
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Review

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22 pages, 1566 KiB  
Review
Understanding Retinoblastoma Post-Translational Regulation for the Design of Targeted Cancer Therapies
by Radoslav Janostiak, Ariadna Torres-Sanchez, Francesc Posas and Eulàlia de Nadal
Cancers 2022, 14(5), 1265; https://doi.org/10.3390/cancers14051265 - 28 Feb 2022
Cited by 7 | Viewed by 3288
Abstract
The retinoblastoma protein (Rb1) is a prototypical tumor suppressor protein whose role was described more than 40 years ago. Together with p107 (also known as RBL1) and p130 (also known as RBL2), the Rb1 belongs to a family of structurally and functionally similar [...] Read more.
The retinoblastoma protein (Rb1) is a prototypical tumor suppressor protein whose role was described more than 40 years ago. Together with p107 (also known as RBL1) and p130 (also known as RBL2), the Rb1 belongs to a family of structurally and functionally similar proteins that inhibits cell cycle progression. Given the central role of Rb1 in regulating proliferation, its expression or function is altered in most types of cancer. One of the mechanisms underlying Rb-mediated cell cycle inhibition is the binding and repression of E2F transcription factors, and these processes are dependent on Rb1 phosphorylation status. However, recent work shows that Rb1 is a convergent point of many pathways and thus the regulation of its function through post-translational modifications is more complex than initially expected. Moreover, depending on the context, downstream signaling can be both E2F-dependent and -independent. This review seeks to summarize the most recent research on Rb1 function and regulation and discuss potential avenues for the design of novel cancer therapies. Full article
(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)
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14 pages, 1313 KiB  
Review
Targeting RB1 Loss in Cancers
by Paing Linn, Susumu Kohno, Jindan Sheng, Nilakshi Kulathunga, Hai Yu, Zhiheng Zhang, Dominic Voon, Yoshihiro Watanabe and Chiaki Takahashi
Cancers 2021, 13(15), 3737; https://doi.org/10.3390/cancers13153737 - 25 Jul 2021
Cited by 23 | Viewed by 7469
Abstract
Retinoblastoma protein 1 (RB1) is encoded by a tumor suppressor gene that was discovered more than 30 years ago. Almost all mitogenic signals promote cell cycle progression by braking on the function of RB1 protein through mono- and subsequent hyper-phosphorylation mediated by cyclin-CDK [...] Read more.
Retinoblastoma protein 1 (RB1) is encoded by a tumor suppressor gene that was discovered more than 30 years ago. Almost all mitogenic signals promote cell cycle progression by braking on the function of RB1 protein through mono- and subsequent hyper-phosphorylation mediated by cyclin-CDK complexes. The loss of RB1 function drives tumorigenesis in limited types of malignancies including retinoblastoma and small cell lung cancer. In a majority of human cancers, RB1 function is suppressed during tumor progression through various mechanisms. The latter gives rise to the acquisition of various phenotypes that confer malignant progression. The RB1-targeted molecules involved in such phenotypic changes are good quarries for cancer therapy. Indeed, a variety of novel therapies have been proposed to target RB1 loss. In particular, the inhibition of a number of mitotic kinases appeared to be synthetic lethal with RB1 deficiency. A recent study focusing on a neighboring gene that is often collaterally deleted together with RB1 revealed a pharmacologically targetable vulnerability in RB1-deficient cancers. Here we summarize current understanding on possible therapeutic approaches targeting functional or genomic aberration of RB1 in cancers. Full article
(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)
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16 pages, 1653 KiB  
Review
Role of the Holoenzyme PP1-SPN in the Dephosphorylation of the RB Family of Tumor Suppressors During Cell Cycle
by Eva M. Verdugo-Sivianes and Amancio Carnero
Cancers 2021, 13(9), 2226; https://doi.org/10.3390/cancers13092226 - 06 May 2021
Cited by 5 | Viewed by 3733
Abstract
Cell cycle progression is highly regulated by modulating the phosphorylation status of the retinoblastoma protein (pRB) and the other two members of the RB family, p107 and p130. This process is controlled by a balance in the action of kinases, such as the [...] Read more.
Cell cycle progression is highly regulated by modulating the phosphorylation status of the retinoblastoma protein (pRB) and the other two members of the RB family, p107 and p130. This process is controlled by a balance in the action of kinases, such as the complexes formed by cyclin-dependent kinases (CDKs) and cyclins, and phosphatases, mainly the protein phosphatase 1 (PP1). However, while the phosphorylation of the RB family has been largely studied, its dephosphorylation is less known. Phosphatases are holoenzymes formed by a catalytic subunit and a regulatory protein with substrate specificity. Recently, the PP1-Spinophilin (SPN) holoenzyme has been described as the main phosphatase responsible for the dephosphorylation of RB proteins during the G0/G1 transition and at the end of G1. Moreover, SPN has been described as a tumor suppressor dependent on PP1 in lung and breast tumors, where it promotes tumorigenesis by increasing the cancer stem cell pool. Therefore, a connection between the cell cycle and stem cell biology has also been proposed via SPN/PP1/RB proteins. Full article
(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)
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13 pages, 3654 KiB  
Review
Direct Regulation of DNA Repair by E2F and RB in Mammals and Plants: Core Function or Convergent Evolution?
by Swarnalatha Manickavinayaham, Briana K. Dennehey and David G. Johnson
Cancers 2021, 13(5), 934; https://doi.org/10.3390/cancers13050934 - 24 Feb 2021
Cited by 3 | Viewed by 3620
Abstract
Members of the E2F transcription factor family regulate the expression of genes important for DNA replication and mitotic cell division in most eukaryotes. Homologs of the retinoblastoma (RB) tumor suppressor inhibit the activity of E2F factors, thus controlling cell cycle progression. Organisms such [...] Read more.
Members of the E2F transcription factor family regulate the expression of genes important for DNA replication and mitotic cell division in most eukaryotes. Homologs of the retinoblastoma (RB) tumor suppressor inhibit the activity of E2F factors, thus controlling cell cycle progression. Organisms such as budding and fission yeast have lost genes encoding E2F and RB, but have gained genes encoding other proteins that take on E2F and RB cell cycle-related functions. In addition to regulating cell proliferation, E2F and RB homologs have non-canonical functions outside the mitotic cell cycle in a variety of eukaryotes. For example, in both mammals and plants, E2F and RB homologs localize to DNA double-strand breaks (DSBs) and directly promote repair by homologous recombination (HR). Here, we discuss the parallels between mammalian E2F1 and RB and their Arabidopsis homologs, E2FA and RB-related (RBR), with respect to their recruitment to sites of DNA damage and how they help recruit repair factors important for DNA end resection. We also explore the question of whether this role in DNA repair is a conserved ancient function of the E2F and RB homologs in the last eukaryotic common ancestor or whether this function evolved independently in mammals and plants. Full article
(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)
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