Modeling Cell Cycle Control and Cancer with pRB Tumor Suppressor

2006 ◽  
pp. 227-256 ◽  
Author(s):  
Lili Yamasaki
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Control

scholarly journals Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 4949-4958 ◽  
Author(s):  
A Hangaishi ◽  
S Ogawa ◽  
N Imamura ◽  
S Miyawaki ◽  
Y Miura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Cell Cycle Control ◽  
Negative Regulators ◽  
Suppressor Genes ◽  
Multiple Tumor ◽  
Lymphoid Malignancies ◽  
Cell Cycle Machinery

It is now evident that the cell cycle machinery has a variety of elements negatively regulating cell cycle progression. However, among these negative regulators in cell cycle control, only 4 have been shown to be consistently involved in the development of human cancers as tumor suppressors: Rb (Retinoblastoma susceptibility protein), p53, and two recently identified cyclin-dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because there are functional interrelations among these negative regulators in the cell cycle machinery, it is particularly interesting to investigate the multiplicity of inactivations of these tumor suppressors in human cancers, including leukemias/lymphomas. To address this point, we examined inactivations of these four genes in primary lymphoid malignancies by Southern blot and polymerase chain reaction-single- strand conformation polymorphism analyses. We also analyzed Rb protein expression by Western blot analysis. The p16INK4A and p15INK4B genes were homozygously deleted in 45 and 42 of 230 lymphoid tumor specimens, respectively. Inactivations of the Rb and p53 genes were 27 of 91 and 9 of 173 specimens, respectively. Forty-one (45.1%) of 91 samples examined for inactivations of all four tumor suppressors had one or more abnormalities of these four tumor-suppressor genes, indicating that dysregulation of cell cycle control is important for tumor development. Statistical analysis of interrelations among impairments of these four genes indicated that inactivations of the individual tumor-suppressor genes might occur almost independently. In some patients, disruptions of multiple tumor-suppressor genes occurred; 4 cases with p16INK4A, p15INK4B, and Rb inactivations; 2 cases with p16INK4A, p15INK4B, and p53 inactivations; and 1 case with Rb and p53 inactivations. It is suggested that disruptions of multiple tumor suppressors in a tumor cell confer an additional growth advantage on the tumor.

scholarly journals ING3 and ING4 immunoexpression and their relation to the development of benign odontogenic lesions

2021 ◽  
Vol 32 (4) ◽  
pp. 74-82
Author(s):  
Yailit del Carmen Martinez-Vargas ◽  
Tiago João da Silva-Filho ◽  
Denise Hélen Imaculada Pereira de Oliveira ◽  
Rani Iani Costa Gonçalo ◽  
Lélia Maria Guedes Queiroz
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Repair ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Gene Family ◽  
Tumor Suppressor Genes ◽  
Cell Cycle Control ◽  
P Value ◽  
Proliferation And Apoptosis

Abstract The Inhibitor of Growth (ING) gene family is a group of tumor suppressor genes that play important roles in cell cycle control, senescence, DNA repair, cell proliferation, and apoptosis. However, inactivation and downregulation of these proteins have been related in some neoplasms. The present study aimed to evaluate the immunohistochemical profiles of ING3 and ING4 proteins in a series of benign epithelial odontogenic lesions. Methods: The sample comprised of 20 odontogenic keratocysts (OKC), 20 ameloblastomas (AM), and 15 adenomatoid odontogenic tumors (AOT) specimens. Nuclear and cytoplasmic immunolabeling of ING3 and ING4 were semi-quantitatively evaluated in epithelial cells of the odontogenic lesions, according to the percentage of immunolabelled cells in each case. Descriptive and statistics analysis were computed, and the p-value was set at 0.05. Results: No statistically significant differences were found in cytoplasmic and nuclear ING3 immunolabeling among the studied lesions. In contrast, AOTs presented higher cytoplasmic and nuclear ING4 labeling compared to AMs (cytoplasmic p-value = 0.01; nuclear p-value < 0.001) and OKCs (nuclear p-value = 0.007). Conclusion: ING3 and ING4 protein downregulation may play an important role in the initiation and progression of more aggressive odontogenic lesions, such as AMs and OKCs.

Polyethylene Glycol - Polyethylenimine Nanoparticle-Mediated Transfection of Mir-150 Into the Leukemia Cells and Determination of the Expression Pattern Changes in Apoptosis and Cell Cycle Genes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4679-4679
Author(s):  
Tugce Balci ◽  
Cigir Biray Avci ◽  
Ipek Ozcan ◽  
Sunde Yilmaz Susluer ◽  
Cagla Kayabasi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Polyethylene Glycol ◽  
Tumor Suppressor ◽  
Expression Pattern ◽  
Cell Lines ◽  
Cell Model ◽  
Cell Cycle Control ◽  
Leukemia Cell ◽  
Gene Expression Pattern ◽  
Leukemia Cells

Abstract Abstract 4679 The aims of this study are transfection of tumor suppressor miR-150 that is down-regulated in leukemogenesis into leukemia cells mediated by Polyethylene Glycol - Polyethylenimine (PEG-PEI) nanoparticle and determine the changes in gene expression pattern in chronic myeloid leukemia model cell lines; K-562 and KU812 and non-leukemia cell lines NCI-BL2347 and NCI-BL2171. Characterization studies and stability studies of PEG-PEI copolymers were performed and by using these copolymers 9 nanoparticle formulations were prepared. Three copolymers (named T1, T3 and T9) were eligible for further analysis and nanoparticle complex (named F1, F2 and F3) formulations, particles that their size less than 300 nM have been evaluated. Nanoparticle-mediated substitution of miR-150 reduced the expressions of cell cycle control genes CDK2 and CCNG2, CDK6 7-fold and 2-fold, respectively in K562 leukemia cell model. Nanoparticle-mediated substitution of miR-150 has been evaluated KU812 leukemia cell model and reduced the expression of cell cycle control genes CHEK2, CDK5RAP1 and CCNG2 and CDKN1A 6- fold 5 –fold and 2-fold, respectively. Substitution of deregulated tumor suppressor miR-150 to leukemia cells with non-viral transfection yielded promising results for the treatment of leukemia. Taking into account these results, it should be supported by preclinical studies in animal models, which would add benefit to current treatment protocols in clinical application. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting EZH2 in Multiple Myeloma—Multifaceted Anti-Tumor Activity

Epigenomes ◽  
2018 ◽  
Vol 2 (3) ◽  
pp. 16 ◽  
Author(s):  
Mohammad Alzrigat ◽  
Helena Jernberg-Wiklund ◽  
Jonathan Licht
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Current Knowledge ◽  
Cell Cycle Control ◽  
Cellular Transformation ◽  
Therapeutic Modality ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Adhesion Properties

The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated with repression of gene expression programs related to stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. EZH2 is deregulated and subjected to gain of function or loss of function mutations, and hence functions as an oncogene or tumor suppressor gene in a context-dependent manner. The development of highly selective inhibitors against the histone methyltransferase activity of EZH2 has also contributed to insight into the role of EZH2 and PRC2 in tumorigenesis, and their potential as therapeutic targets in cancer. EZH2 can function as an oncogene in multiple myeloma (MM) by repressing tumor suppressor genes that control apoptosis, cell cycle control and adhesion properties. Taken together these findings have raised the possibility that EZH2 inhibitors could be a useful therapeutic modality in MM alone or in combination with other targeted agents in MM. Therefore, we review the current knowledge on the regulation of EZH2 and its biological impact in MM, the anti-myeloma activity of EZH2 inhibitors and their potential as a targeted therapy in MM.

scholarly journals PRMT4-Mediated Arginine Methylation Negatively Regulates Retinoblastoma Tumor Suppressor Protein and Promotes E2F-1 Dissociation

2014 ◽  
Vol 35 (1) ◽  
pp. 238-248 ◽  
Author(s):  
Kevin Y. Kim ◽  
Don-Hong Wang ◽  
Mel Campbell ◽  
Steve B. Huerta ◽  
Bogdan Shevchenko ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Posttranslational Modifications ◽  
Transcriptional Activation ◽  
Cell Cycle Control ◽  
Arginine Methylation ◽  
Reporter System ◽  
Suppressor Activity

The retinoblastoma protein (pRb/p105) tumor suppressor plays a pivotal role in cell cycle regulation by blockage of the G1-to-S-phase transition. pRb tumor suppressor activity is governed by a variety of posttranslational modifications, most notably phosphorylation by cyclin-dependent kinase (Cdk) complexes. Here we report a novel regulation of pRb through protein arginine methyltransferase 4 (PRMT4)-mediated arginine methylation, which parallels phosphorylation. PRMT4 specifically methylates pRb at the pRb C-terminal domain (pRb Cterm) on arginine (R) residues R775, R787, and R798in vitroand R787in vivo. Arginine methylation is important for efficient pRb Ctermphosphorylation, as manifested by the reduced phosphorylation of a methylation-impaired mutant, pRb (R3K). A methylmimetic form of pRb, pRb (R3F), disrupts the formation of the E2F-1/DP1-pRb complex in cells as well as in an isolated system. Finally, studies using a Gal4–E2F-1 reporter system show that pRb (R3F) expression reduces the ability of pRb to repress E2F-1 transcriptional activation, while pRb (R3K) expression further represses E2F-1 transcriptional activation relative to that for cells expressing wild-type pRb. Together, our results suggest that arginine methylation negatively regulates the tumor suppressor function of pRb during cell cycle control, in part by creating a better substrate for Cdk complex phosphorylation and disrupting the interaction of pRb with E2F-1.

scholarly journals Stabilization of the Retinoblastoma Protein by A-Type Nuclear Lamins Is Required for INK4A-Mediated Cell Cycle Arrest

2006 ◽  
Vol 26 (14) ◽  
pp. 5360-5372 ◽  
Author(s):  
Ryan T. Nitta ◽  
Samantha A. Jameson ◽  
Brian A. Kudlow ◽  
Lindus A. Conlan ◽  
Brian K. Kennedy
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Lamin A ◽  
Nuclear Lamins ◽  
Cycle Arrest ◽  
Functional Consequences ◽  
Mandibuloacral Dysplasia

ABSTRACT Mutations in the LMNA gene, which encodes all A-type lamins, including lamin A and lamin C, cause a variety of tissue-specific degenerative diseases termed laminopathies. Little is known about the pathogenesis of these disorders. Previous studies have indicated that A-type lamins interact with the retinoblastoma protein (pRB). Here we probe the functional consequences of this association and further examine links between nuclear structure and cell cycle control. Since pRB is required for cell cycle arrest by p16ink4a, we tested the responsiveness of multiple lamin A/C-depleted cell lines to overexpression of this CDK inhibitor and tumor suppressor. We find that the loss of A-type lamin expression results in marked destabilization of pRB. This reduction in pRB renders cells resistant to p16ink4a-mediated G1 arrest. Reintroduction of lamin A, lamin C, or pRB restores p16ink4a-responsiveness to Lmna −/− cells. An array of lamin A mutants, representing a variety of pathologies as well as lamin A processing mutants, was introduced into Lmna −/− cells. Of these, a mutant associated with mandibuloacral dysplasia (MAD R527H), as well as two lamin A processing mutants, but not other disease-associated mutants, failed to restore p16ink4a responsiveness. Although our findings do not rule out links between altered pRB function and laminopathies, they fail to support such an assertion. These findings do link lamin A/C to the functional activation of a critical tumor suppressor pathway and further the possibility that somatic mutations in LMNA contribute to tumor progression.

scholarly journals The tumor-suppressor gene FHIT is involved in the regulation of apoptosis and in cell cycle control

1999 ◽  
Vol 96 (15) ◽  
pp. 8489-8492 ◽  
Author(s):  
L. Sard ◽  
P. Accornero ◽  
S. Tornielli ◽  
D. Delia ◽  
G. Bunone ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Cell Cycle Control ◽  
Suppressor Gene

scholarly journals The tumor suppressor p53 connects ribosome biogenesis to cell cycle control: a double-edged sword

Oncotarget ◽  
2010 ◽  
Vol 1 (1) ◽  
pp. 43-47 ◽  
Author(s):  
Michael Hölzel ◽  
Kaspar Burger ◽  
Bastian Mühl ◽  
Mathias Orban ◽  
Markus Kellner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Ribosome Biogenesis ◽  
Cell Cycle Control ◽  
Tumor Suppressor P53
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