scholarly journals Diversification of Retinoblastoma Protein Function Associated with Cis and Trans Adaptations

2019 ◽  
Vol 36 (12) ◽  
pp. 2790-2804 ◽  
Author(s):  
Rima Mouawad ◽  
Jaideep Prasad ◽  
Dominic Thorley ◽  
Pamela Himadewi ◽  
Dhruva Kadiyala ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Protein Function ◽  
Target Genes ◽  
Cell Cycle Control ◽  
Parallel Evolution ◽  
Retinoblastoma Protein ◽  
Egg Laying ◽  
Vertebrate Lineage ◽  
Transcriptional Corepressors

Abstract Retinoblastoma proteins are eukaryotic transcriptional corepressors that play central roles in cell cycle control, among other functions. Although most metazoan genomes encode a single retinoblastoma protein, gene duplications have occurred at least twice: in the vertebrate lineage, leading to Rb, p107, and p130, and in Drosophila, an ancestral Rbf1 gene and a derived Rbf2 gene. Structurally, Rbf1 resembles p107 and p130, and mutation of the gene is lethal. Rbf2 is more divergent and mutation does not lead to lethality. However, the retention of Rbf2 >60 My in Drosophila points to essential functions, which prior cell-based assays have been unable to elucidate. Here, using genomic approaches, we provide new insights on the function of Rbf2. Strikingly, we show that Rbf2 regulates a set of cell growth-related genes and can antagonize Rbf1 on specific genes. These unique properties have important implications for the fly; Rbf2 mutants show reduced egg laying, and lifespan is reduced in females and males. Structural alterations in conserved regions of Rbf2 gene suggest that it was sub- or neofunctionalized to develop specific regulatory specificity and activity. We define cis-regulatory features of Rbf2 target genes that allow preferential repression by this protein, indicating that it is not a weaker version of Rbf1 as previously thought. The specialization of retinoblastoma function in Drosophila may reflect a parallel evolution found in vertebrates, and raises the possibility that cell growth control is equally important to cell cycle function for this conserved family of transcriptional corepressors.

scholarly journals Diversification of retinoblastoma protein function associated with cis and trans adaptations

2018 ◽  
Author(s):  
Rima Mouawad ◽  
Jaideep Prasad ◽  
Dominic Thorley ◽  
Pamela Himadewi ◽  
Dhruva Kadiyala ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Target Genes ◽  
Growth Control ◽  
Retinoblastoma Protein ◽  
Egg Laying ◽  
Female Reproductive Tract ◽  
Abnormal Development ◽  
Cell Growth Control ◽  
Null Mutants

AbstractRetinoblastoma proteins are eukaryotic transcriptional co-repressors that play central roles in cell cycle control, among other functions. Although most metazoan genomes encode a single retinoblastoma protein, gene duplications have occurred at least twice: in the vertebrate lineage, leading to three genes encoding Rb, p107, and p130, while separately in the Drosophila lineage an ancestral Rbf1 gene and a derived Rbf2 gene. Structurally, Rbf1 resembles p107 and p130 most closely, and mutation of the gene is lethal, while Rbf2 is more divergent, and is not essential for development. Rbf1 has been demonstrated to be a potent repressor of canonical cell-cycle promoters, unlike Rbf2. The retention of Rbf2 over 60 million years in the entire Drosophila lineage points to essential functions, however. We show here that Rbf2 regulates a broad set of cell growth control related genes, and can antagonize Rbf1 on specific sets of promoters. Rbf2 null mutants exhibit abnormal development of the female reproductive tract, with reduced egg laying, while heterozygous null mutants exhibit an increased rate of egg deposition, suggesting that the normal function of this protein is critical for optimal control of fertility. The structural alterations found in conserved regions of the Rbf2 gene suggest that this gene was sub- or neofunctionalized to develop specific regulatory specificity and activity. We define cis regulatory features of Rbf2 target genes that allow preferential repression by this protein, indicating that it is not merely a weaker version of the ancestral protein. The specialization of retinoblastoma function in Drosophila may reflect a parallel evolution found in vertebrates, and raises the possibility that cell growth control is equally important to cell cycle function for this conserved family of transcriptional corepressors.

Human lactoferrin controls the level of retinoblastoma protein and its activityThis paper is one of a selection of papers published in this Special Issue, entitled 7th International Conference on Lactoferrin: Structure, Function, and Applications, and has undergone the Journal's usual peer review process.

2006 ◽  
Vol 84 (3) ◽  
pp. 345-350 ◽  
Author(s):  
Hee-Joung Son ◽  
Shin-Hee Lee ◽  
Sang-Yun Choi
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Kinase Inhibitor ◽  
Peer Review Process ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Cyclin Dependent Kinase ◽  
Antiproliferative Effects ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Selection Of

Lactoferrin (Lf) has been implicated in the regulation of cell growth. However, the molecular mechanism underlying this effect remains to be elucidated. In this study, we show that Lf is involved in the cell cycle control system in a variety of cell lines, through retinoblastoma protein (Rb) - mediated growth arrest. We observed that Lf induces the expression of Rb, a signal mediator of cell cycle control, and that a majority of this Lf-induced Rb persists in a hypophosphorylated form. In addition, we determined that Lf specifically augments the level of a cyclin-dependent kinase inhibitor, p21, but not p27. Upon treatment with Lf, H1299 cells expressing defective p53 effected an augmentation of endogenous p21 levels, which may contribute to the accumulation of hypophosphorylated Rb. A substantial quantity of active Rb binds more efficiently to E2F1 in cells that express Lf and consequently blocks the expression of an E2F1-responsive gene, thereby suggesting that Lf plays a crucial role in the inhibition of tumor cell growth. Therefore, we conclude that the antiproliferative effects of Lf can likely be attributed to the elevated levels of hypophosphorylated Rb.

Retinoblastoma Protein, Gene Expression, and Cell Cycle Control

Cancer Genes ◽  
1996 ◽  
pp. 177-191
Author(s):  
Jane Clifford Azizkhan ◽  
Shiaw Yih Lin ◽  
David Jensen ◽  
Dusan Kostic ◽  
Adrian R. Black
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Protein Gene ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein

scholarly journals Growth Suppression by Acute PromyelocyticLeukemia-Associated Protein PLZF Is Mediated by Repression ofc-mycExpression

2003 ◽  
Vol 23 (24) ◽  
pp. 9375-9388 ◽  
Author(s):  
Melanie J. McConnell ◽  
Nathalie Chevallier ◽  
Windy Berkofsky-Fessler ◽  
Jena M. Giltnane ◽  
Rupal B. Malani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Target Genes ◽  
Ectopic Expression ◽  
Growth Suppression ◽  
Quiescent State ◽  
Cycle Arrest

ABSTRACT The transcriptional repressor PLZF was identified by its translocation with retinoic acid receptor alpha in t(11;17) acute promyelocytic leukemia (APL). Ectopic expression of PLZF leads to cell cycle arrest and growth suppression, while disruption of normal PLZF function is implicated in the development of APL. To clarify the function of PLZF in cell growth and survival, we used an inducible PLZF cell line in a microarray analysis to identify the target genes repressed by PLZF. One prominent gene identified was c-myc. The array analysis demonstrated that repression of c-myc by PLZF led to a reduction in c-myc-activated transcripts and an increase in c-myc-repressed transcripts. Regulation of c-myc by PLZF was shown to be both direct and reversible. An interaction between PLZF and the c-myc promoter could be detected both in vitro and in vivo. PLZF repressed the wild-type c-myc promoter in a reporter assay, dependent on the integrity of the binding site identified in vitro. PLZF binding in vivo was coincident with a decrease in RNA polymerase occupation of the c-myc promoter, indicating that repression occurred via a reduction in the initiation of transcription. Finally, expression of c-myc reversed the cell cycle arrest induced by PLZF. These data suggest that PLZF expression maintains a cell in a quiescent state by repressing c-myc expression and preventing cell cycle progression. Loss of this repression through the translocation that occurs in t(11;17) would have serious consequences for cell growth control.

scholarly journals p18Ink4c and Pten Constrain a Positive Regulatory Loop between Cell Growth and Cell Cycle Control

2006 ◽  
Vol 26 (12) ◽  
pp. 4564-4576 ◽  
Author(s):  
Feng Bai ◽  
Xin-Hai Pei ◽  
Pier Paolo Pandolfi ◽  
Yue Xiong
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Tumor Cells ◽  
Tumor Suppression ◽  
Cell Cycle Control ◽  
Complete Penetrance ◽  
Lipid Phosphatase ◽  
Rb Pathway ◽  
Regulatory Loop ◽  
Prostate Tumor Cells

ABSTRACT Inactivation of the Rb-mediated G1 control pathway is a common event found in many types of human tumors. To test how the Rb pathway interacts with other pathways in tumor suppression, we characterized mice with mutations in both the cyclin-dependent kinase (CDK) inhibitor p18 Ink4c and the lipid phosphatase Pten, which regulates cell growth. The double mutant mice develop a wider spectrum of tumors, including prostate cancer in the anterior and dorsolateral lobes, with nearly complete penetrance and at an accelerated rate. The remaining wild-type allele of Pten was lost at a high frequency in Pten +/− cells but not in p18 +/− Pten +/− or p18 −/− Pten +/− prostate tumor cells, nor in other Pten +/− tumor cells, suggesting a tissue- and genetic background-dependent haploinsufficiency of Pten in tumor suppression. p18 deletion, CDK4 overexpression, or oncoviral inactivation of Rb family proteins caused activation of Akt/PKB that was recessive to the reduction of PTEN activity. We suggest that p18 and Pten cooperate in tumor suppression by constraining a positive regulatory loop between cell growth and cell cycle control pathways.

ATM is involved in cell-cycle control through the regulation of retinoblastoma protein phosphorylation

2010 ◽  
pp. n/a-n/a ◽  
Author(s):  
Javier G. Pizarro ◽  
Jaume Folch ◽  
Aurelio Vazquez de la Torre ◽  
Felix Junyent ◽  
Ester Verdaguer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Phosphorylation ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein

scholarly journals Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27KIP1–Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression

2016 ◽  
Vol 37 (2) ◽  
Author(s):  
Michael J. Thwaites ◽  
Matthew J. Cecchini ◽  
Daniel T. Passos ◽  
Ian Welch ◽  
Frederick A. Dick
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcriptional Repression ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Level Control ◽  
Mutant Genotype ◽  
Single Mutant ◽  
Cdk Regulation

ABSTRACT The mammalian G1-S phase transition is controlled by the opposing forces of cyclin-dependent kinases (CDK) and the retinoblastoma protein (pRB). Here, we present evidence for systems-level control of cell cycle arrest by pRB-E2F and p27-CDK regulation. By introducing a point mutant allele of pRB that is defective for E2F repression (Rb1 G ) into a p27KIP1 null background (Cdkn1b −/−), both E2F transcriptional repression and CDK regulation are compromised. These double-mutant Rb1 G/G ; Cdkn1b −/− mice are viable and phenocopy Rb1 +/− mice in developing pituitary adenocarcinomas, even though neither single mutant strain is cancer prone. Combined loss of pRB-E2F transcriptional regulation and p27KIP1 leads to defective proliferative control in response to various types of DNA damage. In addition, Rb1 G/G ; Cdkn1b −/− fibroblasts immortalize faster in culture and more frequently than either single mutant genotype. Importantly, the synthetic DNA damage arrest defect caused by Rb1 G/G ; Cdkn1b −/− mutations is evident in the developing intermediate pituitary lobe where tumors ultimately arise. Our work identifies a unique relationship between pRB-E2F and p27-CDK control and offers in vivo evidence that pRB is capable of cell cycle control through E2F-independent effects.

scholarly journals The Retinoblastoma Protein Regulates Pericentric Heterochromatin

2006 ◽  
Vol 26 (9) ◽  
pp. 3659-3671 ◽  
Author(s):  
Christian E. Isaac ◽  
Sarah M. Francis ◽  
Alison L. Martens ◽  
Lisa M. Julian ◽  
Laurie A. Seifried ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromatin Structure ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Pericentric Heterochromatin ◽  
Site Mutation ◽  
Histone Tails ◽  
Binding Cleft ◽  
Heterochromatin Structure

ABSTRACT The retinoblastoma protein (pRb) has been proposed to regulate cell cycle progression in part through its ability to interact with enzymes that modify histone tails and create a repressed chromatin structure. We created a mutation in the murine Rb1 gene that disrupted pRb's ability to interact with these enzymes to determine if it affected cell cycle control. Here, we show that loss of this interaction slows progression through mitosis and causes aneuploidy. Our experiments reveal that while the LXCXE binding site mutation does not disrupt pRb's interaction with the Suv4-20h histone methyltransferases, it dramatically reduces H4-K20 trimethylation in pericentric heterochromatin. Disruption of heterochromatin structure in this chromosomal region leads to centromere fusions, chromosome missegregation, and genomic instability. These results demonstrate the surprising finding that pRb uses the LXCXE binding cleft to control chromatin structure for the regulation of events beyond the G1-to-S-phase transition.

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