scholarly journals Iron chelation-induced senescence-like growth arrest in hepatocyte cell lines: association of transforming growth factor β1 (TGF-β1)-mediated p27Kip1 expression

2002 ◽  
Vol 366 (2) ◽  
pp. 613-621 ◽  
Author(s):  
Gyesoon YOON ◽  
Hyun-Jung KIM ◽  
Young-Sil YOON ◽  
Hyeseong CHO ◽  
In K. LIM ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
G1 Arrest ◽  
Cyclin Dependent Kinase ◽  
Negative Cell ◽  
Tgf Β1

Iron is essential for cellular proliferation in all organisms. When deprived of iron, the growth of cells is invariably inhibited. However, the mechanism involved remains largely unclear. In the present study, we have observed that subcytotoxic concentrations of desferroxamine mesylate (DFO), an iron chelator, specifically inhibited the transition from G1 to S-phase of Chang cells, a hepatocyte cell line. This was accompanied by the appearance of senescent biomarkers, such as enlarged and flattened cell morphology, senescence-associated β-galactosidase activity and reduced expression of poly(ADP-ribose) polymerase. Concomitantly, p27Kip1 (where Kip is kinase-inhibitory protein) was induced markedly, whereas other negative cell-cycle regulators, such as p21Cip1 (where Cip is cyclin-dependent kinase-interacting protein), p15INK4B and p16INK4A (where INK is inhibitors of cyclin-dependent kinase 4), were not, implying its association in the G1 arrest. Furthermore, the induction of p27Kip1 was accompanied by an increased level of transforming growth factor β1 (TGF-β1) mRNA. When neutralized with an anti-(TGF-β1) antibody, p27Kip1 induction was completely abolished, indicating that TGF-β1 is the major inducer of p27Kip1. Finally, DFO-induced senescence-like arrest was found to be independent of p53, since cell-cycle arrest was still observed with two p53-negative cell lines, Huh7 and Hep3B cells. In conclusion, DFO induced senescence-like G1 arrest in hepatocyte cell lines and this was associated with the induction of p27Kip1 through TGF-β1, but was independent of p53.

scholarly journals Ligand-Independent Regulation of Transforming Growth Factor β1 Expression and Cell Cycle Progression by the Aryl Hydrocarbon Receptor

2007 ◽  
Vol 27 (17) ◽  
pp. 6127-6139 ◽  
Author(s):  
Xiaoqing Chang ◽  
Yunxia Fan ◽  
Saikumar Karyala ◽  
Sandy Schwemberger ◽  
Craig R. Tomlinson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Transforming Growth Factor Β1 ◽  
Cyclin Dependent Kinase ◽  
Aryl Hydrocarbon ◽  
Tgf Β1

ABSTRACT The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic effects of its xenobiotic ligands and acts as an environmental checkpoint during the cell cycle. We expressed stably integrated, Tet-Off-regulated AHR variants in fibroblasts from AHR-null mice to further investigate the AHR role in cell cycle regulation. Ahr +/+ fibroblasts proliferated significantly faster than Ahr − / − fibroblasts did, and exposure to a prototypical AHR ligand or deletion of the ligand-binding domain did not change their proliferation rates, indicating that the AHR function in cell cycle was ligand independent. Growth-promoting genes, such as cyclin and cyclin-dependent kinase genes, were significantly down-regulated in Ahr − / − cells, whereas growth-arresting genes, such as the transforming growth factor β1 (TGF-β1) gene, extracellular matrix (ECM)-related genes, and cyclin-dependent kinase inhibitor genes, were up-regulated. Ahr − / − fibroblasts secreted significantly more TGF-β1 into the culture medium than Ahr +/+ fibroblasts did, and Ahr − / − showed increased levels of activated Smad4 and TGF-β1 mRNA. Inhibition of TGF-β1 signaling by overexpression of Smad7 reversed the proliferative and gene expression phenotype of Ahr − / − fibroblasts. Changes in TGF-β1 mRNA accumulation were due to stabilization resulting from decreased activity of TTP, the tristetraprolin RNA-binding protein responsible for mRNA destabilization through AU-rich motifs. These results show that the Ah receptor possesses interconnected intrinsic cellular functions, such as ECM formation, cell cycle control, and TGF-β1 regulation, that are independent of activation by either exogenous or endogenous ligands and that may play a crucial role during tumorigenesis.

Suramin inhibits growth and transforming growth factor-β1 (TGF-β1) binding in osteosarcoma cell lines

1994 ◽  
Vol 30 (5) ◽  
pp. 678-682 ◽  
Author(s):  
P. Kloen ◽  
C.L. Jennings ◽  
M.C. Gebhardt ◽  
D.S. Springfield ◽  
H.J. Mankin
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Osteosarcoma Cell ◽  
Tgf Β1

scholarly journals Transforming Growth Factor β1 Receptor II Is Downregulated by E1A in Adenovirus-Infected Cells

2003 ◽  
Vol 77 (17) ◽  
pp. 9324-9336 ◽  
Author(s):  
Vera L. Tarakanova ◽  
William S. M. Wold
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Protein Levels ◽  
Quiescent Cells ◽  
Growth Inhibitory ◽  
Infected Cells ◽  
Cycle Regulation ◽  
Tgf Β1

ABSTRACT Transforming growth factor β1 (TGF-β1) signaling is compromised in many tumors, thereby allowing the tumor to escape the growth-inhibitory and proapoptotic activities of the cytokine. Human adenoviruses interfere with a number of cellular pathways involved in cell cycle regulation and apoptosis, initially placing the cell in a “tumor-like” state by forcing quiescent cells into the cell cycle and also inhibiting apoptosis. We report that adenovirus-infected cells resemble tumor cells in that TGF-β1 signaling is inhibited. The levels of TGF-β1 receptor II (TβRII) in adenovirus-infected cells were decreased, and this decrease was mapped, by using virus mutants, to the E1A gene and to amino acids 2 to 36 and the C-terminal binding protein binding site in the E1A protein. The decrease in the TβRII protein was accompanied by a decrease in TβRII mRNA. The decrease in TβRII protein levels in adenovirus-infected cells was greater than the decrease in TβRII mRNA, suggesting that downregulation of the TβRII protein may occur through more than one mechanism. Surprisingly in this context, the half-lives of the TβRII protein in infected and uninfected cells were similar. TGF-β1 signaling was compromised in cells infected with wild-type adenovirus, as measured with 3TP-lux, a TGF-β-sensitive reporter plasmid expressing luciferase. Adenovirus mutants deficient in TβRII downregulation did not inhibit TGF-β1 signaling. TGF-β1 pretreatment reduced the relative abundance of adenovirus structural proteins in infected cells, an effect that was potentiated when cells were infected with mutants incapable of modulating the TGF-β signaling pathway. These results raise the possibility that inhibition of TGF-β signaling by E1A is a means by which adenovirus counters the antiviral defenses of the host.

scholarly journals Cell Cycle Arrest by Transforming Growth Factor β1 near G1/S Is Mediated by Acute Abrogation of Prereplication Complex Activation Involving an Rb-MCM Interaction

2009 ◽  
Vol 30 (3) ◽  
pp. 845-856 ◽  
Author(s):  
Piyali Mukherjee ◽  
Sherry L. Winter ◽  
Mark G. Alexandrow
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transcriptional Control ◽  
Transforming Growth Factor ◽  
Direct Interaction ◽  
Transforming Growth Factor Β1 ◽  
S Phase ◽  
Mcm Helicase ◽  
Phase Entry ◽  
Tgf Β1

ABSTRACT Understanding inhibitory mechanisms of transforming growth factor β1 (TGF-β1) has provided insight into cell cycle regulation and how TGF-β1 sensitivity is lost during tumorigenesis. We show here that TGF-β1 utilizes a previously unknown mechanism targeting the function of prereplication complexes (pre-RCs) to acutely block S-phase entry when added to cells in late G1, after most G1 events have occurred. TGF-β1 treatment in early G1 suppresses Myc and CycE-Cdk2 and blocks pre-RC assembly. However, TGF-β1 treatment in late G1 acutely blocks S-phase entry by inhibiting activation of fully assembled pre-RCs, with arrest occurring prior to the helicase unwinding step at G1/S. This acute block by TGF-β1 requires the function of Rb in late G1 but does not involve Myc/CycE-Cdk2 suppression or transcriptional control. Instead, Rb mediates TGF-β1 late-G1 arrest by targeting the MCM helicase. Rb binds the MCM complex during late G1 via a direct interaction with Mcm7, and TGF-β1 blocks their dissociation at G1/S. Loss of Rb or overexpression of Mcm7 or its Rb-binding domain alone abrogates late-G1 arrest by TGF-β1. These results demonstrate that TGF-β1 acutely blocks entry into S phase by inhibiting pre-RC activation and suggest a novel role for Rb in mediating this effect of TGF-β1 through direct interaction with and control of the MCM helicase.

scholarly journals Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Hong-Mou Shih ◽  
Szu-Yu Pan ◽  
Chih-Jen Wu ◽  
Yu-Hsiang Chou ◽  
Chun-Yuan Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β1 ◽  
Novel Treatment ◽  
Repressive Effect ◽  
Tgf Β1

Abstract Background Renal erythropoietin (EPO)-producing (REP) cells produce EPO through hypoxia-inducible factor (HIF) 2α-activated gene transcription. Insufficient EPO production leads to anemia in patients with chronic kidney disease. Although recombinant EPO is effective to improve anemia, no reliable REP cell lines limit further progress of research and development of novel treatment. Methods We screened Epo mRNA expression in mouse fibroblast cell lines. Small interfering RNA specific for HIF1α or HIF2α was transfected to study Epo expression in C3H10T1/2 cells. The effect of transforming growth factor-β1 (TGF-β1) on HIF-EPO axis was studied in C3H10T1/2 cells and mice. Results Similar to mouse REP pericytes, C3H10T1/2 cells differentiated to α-smooth muscle actin+ myofibroblasts after exposure to TGF-β1. Specific HIF knockdown demonstrated the role of HIF2α in hypoxia-induced Epo expression. Sustained TGF-β1 exposure increased neither DNA methyltransferase nor methylation of Epas1 and Epo genes. However, TGF-β1 repressed HIF2α-encoding Epas1 promptly through activating activin receptor-like kinase-5 (ALK5), thereby decreasing Epo induction by hypoxia and prolyl hydroxylase domain inhibitor roxadustat. In mice with pro-fibrotic injury induced by ureteral obstruction, upregulation of Tgfb1 was accompanied with downregulation of Epas1 and Epo in injured kidneys and myofibroblasts, which were reversed by ALK5 inhibitor SB431542. Conclusion C3H10T1/2 cells possessed the property of HIF2α-dependent Epo expression in REP pericytes. TGF-β1 induced not only the transition to myofibroblasts but also a repressive effect on Epas1-Epo axis in C3H10T1/2 cells. The repressive effect of TGF-β1 on Epas1-Epo axis was confirmed in REP pericytes in vivo. Inhibition of TGF-β1-ALK5 signaling might provide a novel treatment to rescue EPO expression in REP pericytes of injured kidney.

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