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.

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 Transforming growth factor β1 attenuates ceramide-induced CPP32/Yama activation and apoptosis in human leukaemic HL-60 cells

1997 ◽  
Vol 327 (3) ◽  
pp. 663-667 ◽  
Author(s):  
Min-Liang KUO ◽  
Chien-Wei CHEN ◽  
Shiou-Hwa JEE ◽  
Shuang-En CHUANG ◽  
Ann-Lii CHENG
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Second Messenger ◽  
Transforming Growth Factor Β1 ◽  
Cellular Functions ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induced Apoptosis ◽  
Tgf Β1

Ceramide, a product of sphingomyelin turnover, is a novel lipid second messenger that mediates important cellular functions including proliferation, differentiation and apoptosis. This study demonstrates that the CPP32/Yama protease was activated during apoptosis induced by the membrane-permeable second messenger C2-ceramide in HL-60 cells. We also found that the addition of a specific tetrapeptide inhibitor of CPP32/Yama, Ac-DEVD-CHO, provided an effective protection against ceramide-induced cell death. These results suggested that CPP32/Yama has a central role in ceramide-mediated apoptosis. Furthermore a wide variety of cytokines were examined for their effect on ceramide-induced apoptosis. Only transforming growth factor β1 (TGF-β1) (1 ng/ml) exerted significant prevention of apoptosis induced by C2-ceramide, or by sphingomyelinase (increases intracellular ceramide). Consistently, TGF-β1 abrogated the cleavage of poly(ADP-ribose) polymerase and the production of the CPP32/Yama active subunit, p17. However, TGF-β1 treatment did not cause growth inhibition or alter the level of cyclin-dependent kinase inhibitor p27. It suggests that the preventive effect of TGF-β1 is not mediated by growth arrest. Interestingly, we found that TGF-β1 prevented the C2-ceramide-caused decrease of Bcl-2 protein. We thus propose that TGF-β1 rescues ceramide-induced cell death, possibly by maintaining the constant level of Bcl-2, thereby abolishing CPP32/Yama protease activation.

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.

Cell-Specific Regulation of Human Aryl Hydrocarbon Receptor Expression by Transforming Growth Factor-β1

2001 ◽  
Vol 59 (4) ◽  
pp. 716-724 ◽  
Author(s):  
Sandra Wolff ◽  
Patricia A. Harper ◽  
Judy M. Y. Wong ◽  
Volker Mostert ◽  
Yanping Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Receptor Expression ◽  
Aryl Hydrocarbon ◽  
Specific Regulation

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.

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