scholarly journals Enforced expression of the c-myc oncogene inhibits cell differentiation by precluding entry into a distinct predifferentiation state in G0/G1.

1988 ◽  
Vol 8 (4) ◽  
pp. 1614-1624 ◽  
Author(s):  
S O Freytag
Keyword(s):  
Cell Cycle ◽  
Cell Differentiation ◽  
Transcriptional Control ◽  
Normal Cells ◽  
Myc Oncogene ◽  
Rous Sarcoma ◽  
Myc Gene ◽  
High Concentrations ◽  
Arrest Growth ◽  
Differentiation Inducers

A broad base of data has implicated a role for the c-myc proto-oncogene in the control of the cell cycle and cell differentiation. To further define the role of myc in these processes, I examined the effect of enforced myc expression on several events that are thought to be important steps leading to the terminally differentiated state: (i) the ability to arrest growth in G0/G1, (ii) the ability to replicate the genome upon initiation of the differentiation program, and (iii) the ability to lose responsiveness to mitogens and withdraw from the cell cycle. 3T3-L1 preadipocyte cell lines expressing various levels of myc mRNA were established by transfection with a recombinant myc gene under the transcriptional control of the Rous sarcoma virus (RSV) promoter. Cells that expressed high constitutive levels of pRSVmyc mRNA arrested in G0/G1 at densities similar to those of normal cells at confluence. Upon initiation of the differentiation program, such cells traversed the cell cycle with kinetics similar to those of normal cells and subsequently arrested in G0/G1. Thus, enforced expression of myc had no effect on the ability of cells to arrest growth in G0/G1 or to replicate the genome upon initiation of the differentiation program. Cells were then tested for their ability to reenter the cell cycle upon exposure to high concentrations of serum and for their capacity to differentiate. In contrast to normal cells, cells expressing high constitutive levels of myc RNA reentered the cell cycle when challenged with 30% serum and failed to terminally differentiate. The block to differentiation could be reversed by high expression of myc antisense RNA, showing that the induced block was specifically due to enforced expression of pRSVmyc. These findings indicate that 3T3-L1 preadipocytes enter a specific state in G0/G1 after treatment with differentiation inducers, into which cells expressing high constitutive levels of myc RNA are precluded from entering. I propose that myc acts as a molecular switch and directs cells to a pathway that can lead to continued proliferation or to terminal differentiation.

Enforced expression of the c-myc oncogene inhibits cell differentiation by precluding entry into a distinct predifferentiation state in G0/G1

1988 ◽  
Vol 8 (4) ◽  
pp. 1614-1624
Author(s):  
S O Freytag
Keyword(s):  
Cell Cycle ◽  
Cell Differentiation ◽  
Transcriptional Control ◽  
Normal Cells ◽  
Myc Oncogene ◽  
Rous Sarcoma ◽  
Myc Gene ◽  
High Concentrations ◽  
Arrest Growth ◽  
Differentiation Inducers

A broad base of data has implicated a role for the c-myc proto-oncogene in the control of the cell cycle and cell differentiation. To further define the role of myc in these processes, I examined the effect of enforced myc expression on several events that are thought to be important steps leading to the terminally differentiated state: (i) the ability to arrest growth in G0/G1, (ii) the ability to replicate the genome upon initiation of the differentiation program, and (iii) the ability to lose responsiveness to mitogens and withdraw from the cell cycle. 3T3-L1 preadipocyte cell lines expressing various levels of myc mRNA were established by transfection with a recombinant myc gene under the transcriptional control of the Rous sarcoma virus (RSV) promoter. Cells that expressed high constitutive levels of pRSVmyc mRNA arrested in G0/G1 at densities similar to those of normal cells at confluence. Upon initiation of the differentiation program, such cells traversed the cell cycle with kinetics similar to those of normal cells and subsequently arrested in G0/G1. Thus, enforced expression of myc had no effect on the ability of cells to arrest growth in G0/G1 or to replicate the genome upon initiation of the differentiation program. Cells were then tested for their ability to reenter the cell cycle upon exposure to high concentrations of serum and for their capacity to differentiate. In contrast to normal cells, cells expressing high constitutive levels of myc RNA reentered the cell cycle when challenged with 30% serum and failed to terminally differentiate. The block to differentiation could be reversed by high expression of myc antisense RNA, showing that the induced block was specifically due to enforced expression of pRSVmyc. These findings indicate that 3T3-L1 preadipocytes enter a specific state in G0/G1 after treatment with differentiation inducers, into which cells expressing high constitutive levels of myc RNA are precluded from entering. I propose that myc acts as a molecular switch and directs cells to a pathway that can lead to continued proliferation or to terminal differentiation.

scholarly journals Myc oncogenes: the enigmatic family

1996 ◽  
Vol 314 (3) ◽  
pp. 713-721 ◽  
Author(s):  
Kevin M. RYAN ◽  
George D. BIRNIE
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Cell Cycle Progression ◽  
Target Sequence ◽  
Cycle Progression ◽  
Myc Oncogene ◽  
Human Malignancy ◽  
Myc Gene ◽  
Cellular Quiescence

The myc family of proto-oncogenes is believed to be involved in the establishment of many types of human malignancy. The members of this family have been shown to function as transcription factors, and through a designated target sequence bring about continued cell-cycle progression, cellular immortalization and blockages to differentiation in many lineages. However, while much of the recent work focusing on the c-myc oncogene has provided some very important advances, it has also brought to light a large amount of conflicting data as to the mechanism of action of the gene product. In this regard, it has now been shown that c-myc is effective in transcriptional repression as well as transcriptional activation and, perhaps more paradoxically, that it has a role in programmed cell death (apoptosis) as well as in processes of cell-cycle progression. In addition, particular interest has surrounded the distinct roles of the two alternative translation products of the c-myc gene, c-Myc 1 and c-Myc 2. The intriguing observation that the ratio of c-Myc 1 to c-Myc 2 increases markedly upon cellular quiescence led to the discovery that the enforced expression of the two proteins individually showed that c-Myc 2 stimulates cell growth, whereas c-Myc 1 appears to be growth suppressing. Clearly, the disparities in the activities of c-Myc, together with the consistent occurrence of mutations of c-myc in human malignancies, means that, although reaching an understanding of the functions of the myc gene family might not be simple, it remains well worthy of pursuit.

Reverse Screening Bioinformatics Approach to Identify Potential Anti Breast Cancer Targets Using Thymoquinone from Neutraceuticals Black Cumin Oil

2019 ◽  
Vol 19 (5) ◽  
pp. 599-609 ◽  
Author(s):  
Sumathi Sundaravadivelu ◽  
Sonia K. Raj ◽  
Banupriya S. Kumar ◽  
Poornima Arumugamand ◽  
Padma P. Ragunathan
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Cell Death ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Normal Cells ◽  
Black Cumin ◽  
In Silico Docking ◽  
Wide Range

Background: Functional foods, neutraceuticals and natural antioxidants have established their potential roles in the protection of human health and diseases. Thymoquinone (TQ), the main bioactive component of Nigella sativa seeds (black cumin seeds), a plant derived neutraceutical was used by ancient Egyptians because of their ability to cure a variety of health conditions and used as a dietary food supplement. Owing to its multi targeting nature, TQ interferes with a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Additionally, TQ can specifically sensitize tumor cells towards conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells besides being cost effective and safe. TQ was found to play a protective role when given along with chemotherapeutic agents to normal cells. Methods: In the present study, reverse in silico docking approach was used to search for potential molecular targets for cancer therapy. Various metastatic and apoptotic targets were docked with the target ligand. TQ was also tested for its anticancer activities for its ability to cause cell death, arrest cell cycle and ability to inhibit PARP gene expression. Results: In silico docking studies showed that TQ effectively docked metastatic targets MMPs and other apoptotic and cell proliferation targets EGFR. They were able to bring about cell death mediated by apoptosis, cell cycle arrest in the late apoptotic stage and induce DNA damage too. TQ effectively down regulated PARP gene expression which can lead to enhanced cancer cell death. Conclusion: Thymoquinone a neutraceutical can be employed as a new therapeutic agent to target triple negative breast cancer which is otherwise difficult to treat as there are no receptors on them. Can be employed along with standard chemotherapeutic drugs to treat breast cancer as a combinatorial therapy.

Cell cycle-dependent reactivity with the monoclonal antibody Ki-67 during myeloid cell differentiation

1988 ◽  
Vol 179 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Robert P. Wersto ◽  
Fritz Herz ◽  
Robert E. Gallagher ◽  
Leopold G. Koss
Keyword(s):  
Cell Cycle ◽  
Monoclonal Antibody ◽  
Cell Differentiation ◽  
Myeloid Cell ◽  
Ki 67 ◽  
Cycle Dependent

scholarly journals Phytochemical Analysis and In Vitro Effects of Allium fistulosum L. and Allium sativum L. Extracts on Human Normal and Tumor Cell Lines: A Comparative Study

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 574
Author(s):  
Adrian Bogdan Țigu ◽  
Cristian Silviu Moldovan ◽  
Vlad-Alexandru Toma ◽  
Anca Daniela Farcaș ◽  
Augustin Cătălin Moț ◽  
...  
Keyword(s):  
Cell Line ◽  
Allium Sativum ◽  
Allium Fistulosum ◽  
Tumor Cell Lines ◽  
Sensitive Cell ◽  
Sensitive Cell Line ◽  
Welsh Onion ◽  
Normal Cells ◽  
Ic50 Value ◽  
High Concentrations

Allium sativum L. (garlic bulbs) and Allium fistulosum L. (Welsh onion leaves) showed quantitative differences of identified compounds: allicin and alliin (380 µg/mL and 1410 µg/mL in garlic; 20 µg/mL and 145 µg/mL in Welsh onion), and the phenolic compounds (chlorogenic acid, p-coumaric acid, ferulic acid, gentisic acid, 4-hydroxybenzoic acid, kaempferol, isoquercitrin, quercitrin, quercetin, and rutin). The chemical composition determined the inhibitory activity of Allium extracts in a dose-dependent manner, on human normal cells (BJ-IC50 0.8841% garlic/0.2433% Welsh onion and HaCaT-IC50 1.086% garlic/0.6197% Welsh onion) and tumor cells (DLD-1-IC50 5.482%/2.124%; MDA-MB-231-IC50 6.375%/2.464%; MCF-7-IC50 6.131%/3.353%; and SK-MES-1-IC50 4.651%/5.819%). At high concentrations, the cytotoxic activity of each extract, on normal cells, was confirmed by: the 50% of the growth inhibition concentration (IC50) value, the cell death induced by necrosis, and biochemical determination of LDH, catalase, and Caspase-3. The four tumor cell lines treated with high concentrations (10%, 5%, 2.5%, and 1.25%) of garlic extract showed different sensibility, appreciated on the base of IC50 value for the most sensitive cell line (SK-MES-1), and the less sensitive (MDA-MB-231) cell line. The high concentrations of Welsh onion extract (5%, 2.5%, and 1.25%) induced pH changes in the culture medium and SK-MES-1 being the less sensitive cell line.

scholarly journals Integrin-mediated Activation of Focal Adhesion Kinase Is Required for Signaling to Jun NH2-terminal Kinase and Progression through the G1 Phase of the Cell Cycle

1999 ◽  
Vol 145 (7) ◽  
pp. 1461-1470 ◽  
Author(s):  
Maja Oktay ◽  
Kishore K. Wary ◽  
Michael Dans ◽  
Raymond B. Birge ◽  
Filippo G. Giancotti
Keyword(s):  
Cell Cycle ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
G1 Phase ◽  
Normal Cells ◽  
Jnk Signaling ◽  
Stringent Control ◽  
No Activation ◽  
Stimulation Of

The extracellular matrix exerts a stringent control on the proliferation of normal cells, suggesting the existence of a mitogenic signaling pathway activated by integrins, but not significantly by growth factor receptors. Herein, we provide evidence that integrins cause a significant and protracted activation of Jun NH2-terminal kinase (JNK), while several growth factors cause more modest or no activation of this enzyme. Integrin-mediated stimulation of JNK required the association of focal adhesion kinase (FAK) with a Src kinase and p130CAS, the phosphorylation of p130CAS, and subsequently, the recruitment of Crk. Ras and PI-3K were not required. FAK–JNK signaling was necessary for proper progression through the G1 phase of the cell cycle. These findings establish a role for FAK in both the activation of JNK and the control of the cell cycle, and identify a physiological stimulus for JNK signaling that is consistent with the role of Jun in both proliferation and transformation.

Transcriptional control of delta-crystallin gene expression in the chicken embryo lens: demonstration by a new method for measuring mRNA metabolism

1993 ◽  
Vol 13 (6) ◽  
pp. 3282-3290
Author(s):  
X Li ◽  
D C Beebe
Keyword(s):  
Chicken Embryo ◽  
Transcriptional Control ◽  
Cultured Cells ◽  
Pcr Primers ◽  
High Refractive Index ◽  
In Vitro Transcription ◽  
Equilibrium Density ◽  
Specific Pcr ◽  
High Concentrations

Crystallins are proteins that accumulate to very high concentrations in the fiber cells of the lens of the eye. Crystallins are responsible for the transparency and high refractive index that are essential for lens function. In the chicken embryo, delta-crystallin accounts for more than 70% of the newly synthesized lens proteins. We used density labeling and gene-specific polymerase chain reaction (PCR) to determine the mechanism regulating the expression of the two very similar delta-crystallin genes. Newly synthesized RNA was separated from preexisting RNA by incubating the lenses with 15N- and 13C-labeled ribonucleosides and then separating newly synthesized, density-labeled RNA from the bulk of light RNA by equilibrium density centrifugation in NaI-KI gradients. The relative abundances of the two crystallin mRNAs in the separated fractions were then determined by PCR. This method permitted the quantitation of newly synthesized processed and unprocessed delta-crystallin mRNAs. Additional studies used intron- and gene-specific PCR primers to determine the relative expression of the two delta-crystallin genes in processed RNA and unprocessed RNA extracted from different regions of the embryonic lens. Results of these tests indicated that the differential expression of the delta-crystallin genes was regulated primarily at the level of transcription. This outcome was not expected on the basis of the results of previous studies, which used in vitro transcription and transfection methods to evaluate the relative strengths of delta-crystallin promoter and enhancer sequences. Our data suggest that the cultured cells used in these earlier studies may not have provided an accurate view of delta-crystallin regulation in the intact lens.

scholarly journals Expression of the c-myc proto-oncogene in multiple myeloma and chronic lymphocytic leukemia: an in situ analysis

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 180-191 ◽  
Author(s):  
R Greil ◽  
B Fasching ◽  
P Loidl ◽  
H Huber
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Proliferative Activity ◽  
Plasma Cells ◽  
Lymphocytic Leukemia ◽  
Myc Gene ◽  
Gene Transcripts

Abstract The c-myc gene plays a pivotal role in mediating the competence state for cell cycle transversion. This biologic role is in contradiction to reports of elevated expression of the gene in multiple myeloma, a tumor with restricted self-renewal capacity. To more clearly define the role of this gene in plasma cells of myeloma patients, c-myc messenger RNA (mRNA) and/or oncoprotein expression were semiquantitatively analyzed on the single cell level in 19 cases of multiple myeloma, among them 1 biclonal case and 1 case with coexistent chronic lymphocytic leukemia (CLL). Performing anti-sense/mRNA in situ hybridization, mature c-myc gene transcripts were detected in 92% (12 of 13) of cases and could definitely be attributed to the plasma cells by our study. The number of Ki 67-positive plasma cells actively passing the cell cycle was less than 1% and independent of c-myc gene expression. However, because the presence of the 152-c-MYC epitope was correlated to extent of marrow plasmacytosis (r = .64; P = .043) and content of plasmablasts (P = .09), the c-myc gene might serve a function different from proliferative activity, but also associated with tumor cell mass. In CLL cells (21 of 22 cases) and their benign counterparts, ie, bone marrow and peripheral blood lymphocytes, the anti-sense/c-myc mRNA hybridization signals remained below the threshold considered as cutpoint between negative and positive. The low amounts of c-myc transcripts were correlated to neither stage of disease (P = .52) nor lymphocyte counts (P = .24). Because the numbers of peripheral blood lymphoma cells were independent of tumor mass and of c-myc gene transcripts expressed, peripheral blood lymphocytosis might more likely reflect homing processes than proliferative activity in CLL.

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

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 723-735 ◽  
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.

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