Erol Project Development House for the Disorders of Energy Metabolism

Silivri, Turkey

Erol Project Development House for the Disorders of Energy Metabolism

Silivri, Turkey
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Erol A.,Erol Project Development House for the Disorders of Energy Metabolism
Cell Cycle | Year: 2012

Pyruvate kinase M2 (PKM2) may occur in both a tetrameric and a dimeric form. When the majority of PKM2 molecules are in the highly active tetrameric conformation, glucose is primarily degraded to pyruvate and lactate with the regeneration of energy. A tumor suppressor protein, death-associated protein kinase (DAPK), interacts with PKM2 protein and stabilizes PKM2 in its active tetrameric form in normal proliferating cells. However, DAPK is widely inactivated in cancer cells, leading to the loss of the active conformation of PKM2. This may render PKM2 sensitive to cellular oxidants, switching the enzyme into its inactive dimeric form. Consequently, inhibition of PKM2 after oxidative stress contributes optimal tumor growth and allows cancer cells to withstand oxidative stress. © 2012 Landes Bioscience.


Erol A.,Erol Project Development House for the disorders of energy metabolism
Cellular Signalling | Year: 2011

In response to various types of stress, cells can undergo significant phenotypic changes, ranging from an increased DNA repair to senescence and apoptosis. The mechanisms by which p53 manages the choice between three possible cell fates in response to damaging stress remain poorly understood. p53 is not a simple switch that determines cell fate single-handedly; but rather as a component, albeit an important one, of an intricate signal network and molecular interactions. Thus, in addition to p53, fine-tuned interactions between growth- and division-activator molecules such as TGFβ, cMyc and FOXO are important determinants of the cellular fate. The aim of the paper is to resolve the complex interactions between these molecules and to elicit clear and reasonable working mechanisms for these diverse cellular processes. © 2010 Elsevier Inc.


Erol A.,Erol Project Development House for the Disorders of Energy Metabolism
Cell Cycle | Year: 2011

Genomic integrity maintenance is critical for prevention of a wide variety of adverse cellular effects including apoptosis, cellular senescence and malignant cell transformation. Coupled with normal replication, the local intracellular and extracellular stresses cause damage to cellular DNA that is recognized and repaired by the DNA damage response (DDR) pathway. p53 induces the transcription of genes that negatively regulate progression of the cell cycle in response to DNA damage, and thus participates in maintaining genome stability. p53 and many other anti-proliferative factors such as TGFβ regulate the expression of different cyclin-dependent kinase inhibitors (CDKIs). Paradoxically, one of the cellular proliferative factors, c-Myc proto-oncogene also controls the expression of these CDKIs and modulates the fate of cell in response to DNA damage. Furthermore, involvement of numerous other proteins in the DDR and crosstalk between them are likely to substantiate the DDR as one of the genome's most extensive signaling networks. Versatile protein kinases in this network affect the decision about four basic cellular fates, which are quiescence, apoptosis, oncogenesis and senescence, in response to DNA damage. © 2011 Landes Bioscience.


Erol A.,Erol Project Development House for the Disorders of Energy Metabolism
Current Molecular Medicine | Year: 2010

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. DNA damage in response to genotoxic and oncogenic stresses activate the tumor suppressor pathways initiating DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence. On the other hand, DDR reasons in adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disrupt the existing cellular homeostasis. Significant metabolic changes occurred by the influence of the major tumor suppressor protein p53 and other related factors such as FOXO, AMPK, PARP, NF-κB and PGC-1 are discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that "metabolic syndrome" is a real disease. © 2010 Bentham Science Publishers Ltd.


Erol A.,Erol Project Development House for the Disorders of Energy Metabolism
Medical Hypotheses | Year: 2010

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. Genotoxic and oncogenic stresses-induced DNA damage activate the tumor suppressor pathways initiate DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence and adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disorder the existing cellular homeostasis. This is a disease state similar to metabolic syndrome occurred by the systemic DDR to inhibit ongoing malignant transformation. Significant metabolic changes occurred by the influence of the major tumor suppressor proteins p53 and FOXO discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that "metabolic syndrome" is a real disease. © 2010 Elsevier Ltd.


PubMed | Erol Project Development House for the Disorders of Energy Metabolism
Type: Journal Article | Journal: Medical hypotheses | Year: 2010

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. Genotoxic and oncogenic stresses-induced DNA damage activate the tumor suppressor pathways initiate DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence and adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disorder the existing cellular homeostasis. This is a disease state similar to metabolic syndrome occurred by the systemic DDR to inhibit ongoing malignant transformation. Significant metabolic changes occurred by the influence of the major tumor suppressor proteins p53 and FOXO discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that metabolic syndrome is a real disease.


PubMed | Erol Project Development House for the disorders of energy metabolism
Type: Journal Article | Journal: Cellular signalling | Year: 2011

In response to various types of stress, cells can undergo significant phenotypic changes, ranging from an increased DNA repair to senescence and apoptosis. The mechanisms by which p53 manages the choice between three possible cell fates in response to damaging stress remain poorly understood. p53 is not a simple switch that determines cell fate single-handedly; but rather as a component, albeit an important one, of an intricate signal network and molecular interactions. Thus, in addition to p53, fine-tuned interactions between growth- and division-activator molecules such as TGF, cMyc and FOXO are important determinants of the cellular fate. The aim of the paper is to resolve the complex interactions between these molecules and to elicit clear and reasonable working mechanisms for these diverse cellular processes.


PubMed | Erol Project Development House for the Disorders of Energy Metabolism
Type: Journal Article | Journal: Cell cycle (Georgetown, Tex.) | Year: 2011

Genomic integrity maintenance is critical for prevention of a wide variety of adverse cellular effects including apoptosis, cellular senescence, and malignant cell transformation. Coupled with normal replication, the local intracellular and extracellular stresses cause damage to cellular DNA that is recognized and repaired by the DNA damage response (DDR) pathway. p53 induces the transcription of genes that negatively regulate progression of the cell cycle in response to DNA damage, and thus participates in maintaining genome stability. p53 and many other anti-proliferative factors such as TGF beta regulate the expression of different cyclin-dependent kinase inhibitors (CDKIs). Paradoxically, one of the cellular proliferative factors, c-Myc proto-oncogene also controls the expression of these CDKIs and modulates the fate of cell in response to DNA damage. Furthermore, involvement of numerous other proteins in the DDR and crosstalk between them are likely to substantiate the DDR as one of the genomes most extensive signaling networks. Versatile protein kinases in this network affect the decision about four basic cellular fates, which are quiescence, apoptosis, oncogenesis and senescence, in response to DNA damage.


PubMed | Erol Project Development House for the Disorders of Energy Metabolism
Type: Journal Article | Journal: Cell cycle (Georgetown, Tex.) | Year: 2012

Pyruvate kinase M2 (PKM2) may occur in both a tetrameric and a dimeric form. When the majority of PKM2 molecules are in the highly active tetrameric conformation, glucose is primarily degraded to pyruvate and lactate with the regeneration of energy. A tumor suppressor protein, death-associated protein kinase (DAPK), interacts with PKM2 protein and stabilizes PKM2 in its active tetrameric form in normal proliferating cells. However, DAPK is widely inactivated in cancer cells, leading to the loss of the active conformation of PKM2. This may render PKM2 sensitive to cellular oxidants, switching the enzyme into its inactive dimeric form. Consequently, inhibition of PKM2 after oxidative stress contributes optimal tumor growth and allows cancer cells to withstand oxidative stress.


PubMed | Erol Project Development House for the Disorders of Energy Metabolism
Type: Journal Article | Journal: Current molecular medicine | Year: 2013

The importance of Akt, Erk, and their downstream effectors-mediated signaling is indisputable for the proliferation of cell. Growth factor-induced activation of Akt and Erk pathways interacts with each other to regulate proliferation. However, an instructive model, wiring the crucial signaling nodes working in cellular growth and division, is still absent or controversial. Although growth factor-mediated mTORC1 regulation is defined considerably, debates still exist formTORC2. TSC1-TSC2 complex integrates both nutrient and mitogenic signals coming from growth factor receptors. Growth factor-induced PI3K/Akt- and Ras/Erk-mediated TSC2 inhibition is well defined. However, the interaction between TSC complex and new molecules such as Pin1 and DAPK requires further clarifications. Furthermore, the Wnt--catenin signaling pathway also intersects with the growth factor signaling at TSC1/TSC2 junction. Therefore, the aim of this perspective paper is to suggest an integrated model, linking growth factor-activated crucial signaling nodes in order to supply key molecular connections to degenerative diseases.

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