Genomic components of carcinogenesis

Abstract Many of the genes encoding growth factors, growth factor receptors, enzymes, and other effector molecules that regulate normal cell growth are designated protooncogenes. Oncogenes, those genes associated with cellular transformation, differ from their protooncogenic progenitors by being mutated, overexpressed, or expressed at inappropriate times or locations in the cell. One of the activities of growth factors is to prime cells to undergo programmed cell death, which is characterized by a series of morphologic changes called apoptosis. In normal cells, specific mediators must be activated or suppressed to bypass programmed cell death. In tumor cells, either the pathways leading to apoptosis are not functional or the mediators that normally "rescue" cells from this fate are overexpressed or constitutively activated. In addition to the biochemical pathways that drive cell division, there are others that limit cell proliferation; these, designated tumor suppressors, anti-oncogenes, or recessive oncogenes, must be inactivated in normal cells to allow passage through the cell cycle and cell proliferation. In contrast to oncogenes, which are overexpressed or activated in tumors, tumor-suppressor genes are frequently inactivated in tumor cells, either by mutation or deletion. Thus, in normal cells a series of checks and balances must be overcome to allow initiation and continuation of cell division. In tumors, these processes are aberrant, resulting in increased rates of cell division, increases in the proportion of cells in the cell cycle, or increased survival of activated cells. Therefore, tumor cells frequently accumulate genomic alterations, which may result in the activation of a particular array of oncogenes, the inactivation of specific tumor-suppressor genes, and the bypassing of programmed cell death. Trials of antitumor agents that act by exploiting the overexpression of oncogenes in tumors and of the biochemical pathways by which they mediate cell proliferation are currently underway.

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Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death.

Journal of Experimental Medicine ◽

10.1084/jem.183.5.2219 ◽

1996 ◽

Vol 183 (5) ◽

pp. 2219-2226 ◽

Cited By ~ 199

Author(s):

S Mazel ◽

D Burtrum ◽

H T Petrie

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Division ◽

Programmed Cell Death ◽

Cell Cycle Progression ◽

Control Point ◽

Cell Division Cycle ◽

Cell Cycle Distribution ◽

Cycle Progression ◽

Critical Control Point

Expression of the bcl-2 gene has been shown to effectively confer resistance to programmed cell death under a variety of circumstances. However, despite a wealth of literature describing this phenomenon, very little is known about the mechanism of resistance. In the experiments described here, we show that bcl-2 gene expression can result in an inhibition of cell division cycle progression. These findings are based upon the analysis of cell cycle distribution, cell cycle kinetics, and relative phosphorylation of the retinoblastoma tumor suppressor protein, using primary tissues in vivo, ex vivo, and in vitro, as well as continuous cell lines. The effects of bcl-2 expression on cell cycle progression appear to be focused at the G1 to S phase transition, which is a critical control point in the decision between continued cell cycle progression or the induction programmed cell death. In all systems tested, bcl-2 expression resulted in a substantial 30-60% increase in the length of G1 phase; such an increase is very substantial in the context of other regulators of cell cycle progression. Based upon our findings, and the related findings of others, we propose a mechanism by which bcl-2 expression might exert its well known inhibition of programmed cell death by regulating the kinetics of cell cycle progression at a critical control point.

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Death in the Life of a Tooth

Journal of Dental Research ◽

10.1177/154405910408300103 ◽

2004 ◽

Vol 83 (1) ◽

pp. 11-16 ◽

Cited By ~ 55

Author(s):

E. Matalova ◽

A.S. Tucker ◽

P.T. Sharpe

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Cell Division ◽

Programmed Cell Death ◽

Tooth Development ◽

Cell Number ◽

Substantial Evidence ◽

Bud Formation ◽

Dental Lamina ◽

Tooth Buds

Programmed cell death (apoptosis) constitutes an important mechanism in embryonic development. Although there is substantial evidence for essential roles of apoptosis in organ shaping and controlling of cell number, the mechanisms of these processes are poorly understood. The regulation of cell proliferation to form tooth buds of the appropriate size and at the correct positions must involve a balance between cell division and cell death. Apoptosis has been suggested to play both passive and active roles in bud formation and morphogenesis and in reduction of the dental lamina, as well as silencing of the enamel knot signaling centers. The location of apoptotic cells during tooth development has been described and suggests their temporospatial roles. Unfortunately, there is little functional evidence on these roles, and the aim of this review is to highlight areas where apoptosis may play key roles in odontogenesis.

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Many Genomic Regions Are Required for Normal Embryonic Programmed Cell Death in Caenorhabditis elegans

Genetics ◽

10.1093/genetics/158.1.237 ◽

2001 ◽

Vol 158 (1) ◽

pp. 237-252

Author(s):

Asako Sugimoto ◽

Ayumi Kusano ◽

Rebecca R Hozak ◽

W Brent Derry ◽

Jiangwen Zhu ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Cell Division ◽

Caenorhabditis Elegans ◽

Programmed Cell Death ◽

Embryonic Cell ◽

Direct Result ◽

Class Iii ◽

Cell Corpse ◽

Genomic Regions

Abstract To identify genes involved in programmed cell death (PCD) in Caenorhabditis elegans, we screened a comprehensive set of chromosomal deficiencies for alterations in the pattern of PCD throughout embryonic development. From a set of 58 deficiencies, which collectively remove ∼74% of the genome, four distinct classes were identified. In class I (20 deficiencies), no significant deviation from wild type in the temporal pattern of cell corpses was observed, indicating that much of the genome does not contain zygotic genes that perform conspicuous roles in embryonic PCD. The class II deficiencies (16 deficiencies defining at least 11 distinct genomic regions) led to no or fewer-than-normal cell corpses. Some of these cause premature cell division arrest, probably explaining the diminution in cell corpse number; however, others have little effect on cell proliferation, indicating that the reduced cell corpse number is not a direct result of premature embryonic arrest. In class III (18 deficiencies defining at least 16 unique regions), an excess of cell corpses was observed. The developmental stage at which the extra corpses were observed varied among the class III deficiencies, suggesting the existence of genes that perform temporal-specific functions in PCD. The four deficiencies in class IV (defining at least three unique regions), showed unusually large corpses that were, in some cases, attributable to extremely premature arrest in cell division without a concomitant block in PCD. Deficiencies in this last class suggest that the cell death program does not require normal embryonic cell proliferation to be activated and suggest that while some genes required for cell division might also be required for cell death, others are not. Most of the regions identified by these deficiencies do not contain previously identified zygotic cell death genes. There are, therefore, a substantial number of as yet unidentified genes required for normal PCD in C. elegans.

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

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190124155359 ◽

2019 ◽

Vol 19 (5) ◽

pp. 599-609 ◽

Cited By ~ 1

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.

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Receptor Tyrosine Kinases: Role in Cancer Progression

Current Oncology ◽

10.3390/curroncol13050019 ◽

2006 ◽

Vol 13 (5) ◽

pp. 191-193

Author(s):

V. Sangwan ◽

M. Park

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Programmed Cell Death ◽

Cancer Progression ◽

Tyrosine Kinases ◽

Normal Tissue ◽

Receptor Tyrosine Kinases ◽

Tight Control ◽

Tissue Patterning

Tight control of cell proliferation and morphogenesis in conjunction with programmed cell death (apoptosis) is required to ensure normal tissue patterning. [...]

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SOG1 transcription factor promotes the onset of endoreduplication under salinity stress in Arabidopsis

Scientific Reports ◽

10.1038/s41598-021-91293-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kalyan Mahapatra ◽

Sujit Roy

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Death ◽

Transcription Factor ◽

Programmed Cell Death ◽

Salinity Stress ◽

Crucial Role ◽

Genome Stability ◽

Cell Cycle Checkpoint ◽

Cell Cycle Regulators

AbstractAs like in mammalian system, the DNA damage responsive cell cycle checkpoint functions play crucial role for maintenance of genome stability in plants through repairing of damages in DNA and induction of programmed cell death or endoreduplication by extensive regulation of progression of cell cycle. ATM and ATR (ATAXIA-TELANGIECTASIA-MUTATED and -RAD3-RELATED) function as sensor kinases and play key role in the transmission of DNA damage signals to the downstream components of cell cycle regulatory network. The plant-specific NAC domain family transcription factor SOG1 (SUPPRESSOR OF GAMMA RESPONSE 1) plays crucial role in transducing signals from both ATM and ATR in presence of double strand breaks (DSBs) in the genome and found to play crucial role in the regulation of key genes involved in cell cycle progression, DNA damage repair, endoreduplication and programmed cell death. Here we report that Arabidopsis exposed to high salinity shows generation of oxidative stress induced DSBs along with the concomitant induction of endoreduplication, displaying increased cell size and DNA ploidy level without any change in chromosome number. These responses were significantly prominent in SOG1 overexpression line than wild-type Arabidopsis, while sog1 mutant lines showed much compromised induction of endoreduplication under salinity stress. We have found that both ATM-SOG1 and ATR-SOG1 pathways are involved in the salinity mediated induction of endoreduplication. SOG1was found to promote G2-M phase arrest in Arabidopsis under salinity stress by downregulating the expression of the key cell cycle regulators, including CDKB1;1, CDKB2;1, and CYCB1;1, while upregulating the expression of WEE1 kinase, CCS52A and E2Fa, which act as important regulators for induction of endoreduplication. Our results suggest that Arabidopsis undergoes endoreduplicative cycle in response to salinity induced DSBs, showcasing an adaptive response in plants under salinity stress.

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Suppression of cell proliferation and programmed cell death by dexamethasone during postnatal lung development

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00406.2000 ◽

2002 ◽

Vol 282 (3) ◽

pp. L477-L483 ◽

Cited By ~ 31

Author(s):

Cédric Luyet ◽

Peter H. Burri ◽

Johannes C. Schittny

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Programmed Cell Death ◽

Lung Development ◽

Structural Changes ◽

Tissue Transglutaminase ◽

Lung Parenchyma ◽

Lung Maturation ◽

Morphological Criteria ◽

Postnatal Lung Development

Prematurely born babies are often treated with glucocorticoids. We studied the consequences of an early postnatal and short dexamethasone treatment (0.1–0.01 μg/g, days 1–4) on lung development in rats, focusing on its influence on peaks of cell proliferation around day 4 and of programmed cell death at days 19–21. By morphological criteria, we observed a dexamethasone-induced premature maturation of the septa ( day 4), followed by a transient septal immatureness and delayed alveolarization leading to complete rescue of the structural changes. The numbers of proliferating (anti-Ki67) and dying cells (TdT-mediated dUTP nick end labeling) were determined and compared with controls. In dexamethasone-treated animals, both the peak of cell proliferation and the peak of programmed cell death were reduced to baseline, whereas the expression of tissue transglutaminase (transglutaminase-C), another marker for postnatal lung maturation, was not significantly altered. We hypothesize that a short neonatal course of dexamethasone leads to severe but transient structural changes of the lung parenchyma and influences the balance between cell proliferation and cell death even in later stages of lung maturation.

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