The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death

Mutations that result in the loss of function of pRB were first identified in retinoblastoma and since then have been associated with the propagation of various forms of cancer. pRB is best known for its key role as a transcriptional regulator during cell cycle exit. Beyond the ability of pRB to regulate transcription of cell cycle progression genes, pRB can remodel chromatin to exert several of its other biological roles. In this review, we discuss the diverse functions of pRB in epigenetic regulation including nucleosome mobilization, histone modifications, DNA methylation and non-coding RNAs.

Download Full-text

Identification of G1 kinase activity for cdk6, a novel cyclin D partner.

Molecular and Cellular Biology ◽

10.1128/mcb.14.3.2077 ◽

1994 ◽

Vol 14 (3) ◽

pp. 2077-2086 ◽

Cited By ~ 454

Author(s):

M Meyerson ◽

E Harlow

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Kinase Activity ◽

Suppressor Gene ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

Retinoblastoma Tumor Suppressor ◽

Cell Extracts ◽

Retinoblastoma Tumor ◽

Cycle Regulation

A family of vertebrate cdc2-related kinases has been identified, and these kinases are candidates for roles in cell cycle regulation. Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. Furthermore, we demonstrate that endogenous cdk6 from human cell extracts is an active kinase which can phosphorylate pRB, the product of the retinoblastoma tumor suppressor gene. The activation of cdk6 kinase occurs during mid-G1 in phytohemagglutinin-stimulated T cells, well prior to the activation of cdk2 kinase. This timing suggests that cdk6, and by analogy its homolog cdk4, links growth factor stimulation with the onset of cell cycle progression.

Download Full-text

Identification of G1 kinase activity for cdk6, a novel cyclin D partner

Molecular and Cellular Biology ◽

10.1128/mcb.14.3.2077-2086.1994 ◽

1994 ◽

Vol 14 (3) ◽

pp. 2077-2086

Author(s):

M Meyerson ◽

E Harlow

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Kinase Activity ◽

Suppressor Gene ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

Retinoblastoma Tumor Suppressor ◽

Cell Extracts ◽

Retinoblastoma Tumor ◽

Cycle Regulation

A family of vertebrate cdc2-related kinases has been identified, and these kinases are candidates for roles in cell cycle regulation. Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. Furthermore, we demonstrate that endogenous cdk6 from human cell extracts is an active kinase which can phosphorylate pRB, the product of the retinoblastoma tumor suppressor gene. The activation of cdk6 kinase occurs during mid-G1 in phytohemagglutinin-stimulated T cells, well prior to the activation of cdk2 kinase. This timing suggests that cdk6, and by analogy its homolog cdk4, links growth factor stimulation with the onset of cell cycle progression.

Download Full-text

Faculty Opinions recommendation of The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006699.83556 ◽

2002 ◽

Author(s):

Andrius Kazlauskas

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Cycle Progression

Download Full-text

SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

Blood ◽

10.1182/blood-2011-01-328765 ◽

2011 ◽

Vol 118 (3) ◽

pp. 723-735 ◽

Cited By ~ 28

Author(s):

Hedia Chagraoui ◽

Mira Kassouf ◽

Sreemoti Banerjee ◽

Nicolas Goardon ◽

Kevin Clark ◽

...

Keyword(s):

Cell Cycle ◽

Transcriptional Control ◽

Cell Cycle Progression ◽

Cellular Proliferation ◽

Loss Of Function ◽

Cycle Progression ◽

Cell Cycle Regulator ◽

Nuclear Changes ◽

Cytoplasmic Maturation

Abstract Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.

Download Full-text

The Activity of Differentiation Factors Induces Apoptosis in Polyomavirus Large T-Expressing Myoblasts

Molecular Biology of the Cell ◽

10.1091/mbc.9.6.1449 ◽

1998 ◽

Vol 9 (6) ◽

pp. 1449-1463 ◽

Cited By ~ 22

Author(s):

Gian Maria Fimia ◽

Vanesa Gottifredi ◽

Barbara Bellei ◽

Maria Rosaria Ricciardi ◽

Agostino Tafuri ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Growth Factor ◽

Cell Cycle Progression ◽

Transforming Growth Factor ◽

Myogenic Differentiation ◽

Transforming Growth Factor Β ◽

Large Tumor ◽

Cycle Progression

It is commonly accepted that pathways that regulate proliferation/differentiation processes, if altered in their normal interplay, can lead to the induction of programmed cell death. In a previous work we reported that Polyoma virus Large Tumor antigen (PyLT) interferes with in vitro terminal differentiation of skeletal myoblasts by binding and inactivating the retinoblastoma antioncogene product. This inhibition occurs after the activation of some early steps of the myogenic program. In the present work we report that myoblasts expressing wild-type PyLT, when subjected to differentiation stimuli, undergo cell death and that this cell death can be defined as apoptosis. Apoptosis in PyLT-expressing myoblasts starts after growth factors removal, is promoted by cell confluence, and is temporally correlated with the expression of early markers of myogenic differentiation. The block of the initial events of myogenesis by transforming growth factor β or basic fibroblast growth factor prevents PyLT-induced apoptosis, while the acceleration of this process by the overexpression of the muscle-regulatory factor MyoD further increases cell death in this system. MyoD can induce PyLT-expressing myoblasts to accumulate RB, p21, and muscle- specific genes but is unable to induce G00arrest. Several markers of different phases of the cell cycle, such as cyclin A, cdk-2, and cdc-2, fail to be down-regulated, indicating the occurrence of cell cycle progression. It has been frequently suggested that apoptosis can result from an unbalanced cell cycle progression in the presence of a contrasting signal, such as growth factor deprivation. Our data involve differentiation pathways, as a further contrasting signal, in the generation of this conflict during myoblast cell apoptosis.

Download Full-text

The RASSF6 Tumor Suppressor Protein Regulates Apoptosis and Cell Cycle Progression via Retinoblastoma Protein

Molecular and Cellular Biology ◽

10.1128/mcb.00046-18 ◽

2018 ◽

Vol 38 (17) ◽

Cited By ~ 2

Author(s):

Shakhawoat Hossain ◽

Hiroaki Iwasa ◽

Aradhan Sarkar ◽

Junichi Maruyama ◽

Kyoko Arimoto-Matsuzaki ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Cell Cycle Arrest ◽

Cell Cycle Progression ◽

Target Genes ◽

Loss Of Function ◽

Cycle Progression ◽

P53 Expression ◽

Cycle Arrest ◽

Hct116 Cells

ABSTRACT RASSF6 is a member of the tumor suppressor Ras association domain family (RASSF) proteins. RASSF6 is frequently suppressed in human cancers, and its low expression level is associated with poor prognosis. RASSF6 regulates cell cycle arrest and apoptosis and plays a tumor suppressor role. Mechanistically, RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. However, RASSF6 also induces cell cycle arrest and apoptosis in a p53-negative background, which implies that the tumor suppressor function of RASSF6 does not depend solely on p53. In this study, we revealed that RASSF6 mediates cell cycle arrest and apoptosis via pRb. RASSF6 enhances the interaction between pRb and protein phosphatase. RASSF6 also enhances P16INK4A and P14ARF expression by suppressing BMI1. In this way, RASSF6 increases unphosphorylated pRb and augments the interaction between pRb and E2F1. Moreover, RASSF6 induces TP73 target genes via pRb and E2F1 in a p53-negative background. Finally, we confirmed that RASSF6 depletion induces polyploid cells in p53-negative HCT116 cells. In conclusion, RASSF6 behaves as a tumor suppressor in cancers with loss of function of p53, and pRb is implicated in this function of RASSF6.

Download Full-text

Anticancer Activity of Cynomorium coccineum

Cancers ◽

10.3390/cancers10100354 ◽

2018 ◽

Vol 10 (10) ◽

pp. 354 ◽

Cited By ~ 7

Author(s):

Mouna Sdiri ◽

Xiangmin Li ◽

William Du ◽

Safia El-Bok ◽

Yi-Zhen Xie ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Anticancer Activity ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cell Cycle Progression ◽

Cycle Progression

The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum’s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds.

Download Full-text

Antiproliferative activities of tricyclic amides derived from β-caryophyllene via the Ritter reaction against MDA-MB-231 breast cancer cells

RSC Medicinal Chemistry ◽

10.1039/c9md00237e ◽

2020 ◽

Vol 11 (1) ◽

pp. 118-124 ◽

Cited By ~ 1

Author(s):

XiXi Xu ◽

Ariane Roseblade ◽

Tristan Rawling ◽

Alison T. Ung

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Death ◽

Breast Cancer Cells ◽

Cell Cycle Progression ◽

Apoptotic Cell ◽

Ritter Reaction ◽

Cycle Progression ◽

The Ritter Reaction ◽

Antiproliferative Activities

Tricyclic amides were successfully synthesised from β-caryophyllene via the Ritter reaction. Amides 3c and 6b inhibited proliferation of MDA-MB-231 cells. Compound 6b inhibited cell cycle progression and induced predominantly apoptotic cell death.

Download Full-text