Transforming Growth Factor-β1 Induces Apoptosis through Down-Regulation of c-mycGene and Overexpression of p27Kip1Protein in Cervical Carcinoma

Kim, Jin Woo; Kim, Ho Shik; Kim, In Kyung; Kim, Mee‐Ran; Cho, Eun Young; Kim, Heung Kee; Lee, Joon Mo; Namkoong, Sung Eun

doi:10.1006/gyno.1998.5003

Cited by 34 publications

(18 citation statements)

References 29 publications

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“…17,18 One characteristic associated with malignant progression of cervical epithelial cells is their progressive loss of responsiveness to TGF-β1. 3,4 Furthermore, resistance to TGF-β1 that is acquired by several cell lines correlates with HPV tumorigenic potential. Such studies indicate that after HPV infection, additional cellular or molecular changes might participate in the loss of TGF-β responsiveness, which then promotes malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

“…A particularly interesting biological characteristic associated with carcinogenesis of cervical epithelial cells is their progressive loss of responsiveness to transforming growth factor-β (TGF-β). 3,4 TGF-β is a member of a multifunctional family of growth factors that regulate basic cellular functions, such as proliferation, apoptosis, differentiation, extracellular matrix turnover and immunosuppression. 5 One of the most widely studied roles of TGF-β is its function as a tumor suppressor.…”

Section: Introductionmentioning

confidence: 99%

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Expression and mutational analysis of TGF-β/Smads signaling in human cervical cancers

Tong

Huh

et al. 2009

J Gynecol Oncol

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Objective: To define the molecular basis of TGF-β1 function in cervical carcinogenesis, we explored the expression and mutational status of TGF-β1, TGF-β1 receptors, and Smads, the regulators of the TGF-β1 signaling pathway, in human cervical cancers. Methods: Expression of TGF-β1, TGF-β1 receptors, and Smads transcripts were determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR), and sequence alteration was analyzed using RT-PCR-single-strand conformation polymorphism (SSCP) analysis. Genomic levels of TGF-β1, TGF-β1 receptors and Smads was also measured by quantitative genomic PCR. Results: Abnormal overexpression of TGF-β1 and abnormal reduction of type II TGF-β1 receptor were identified in 36% (18 of 50) and 20% (10 of 50) of cervical cancer tissues, respectively. 22% (11 of 50) in Smad2 and 14% (7 of 50) in Smad4 revealed tumor specific mRNA reduction less than a half of normal means. In addition, no evidence for sequence alterations of the gene was found by RT-PCR-SSCP analysis. Conclusion: Our study demonstrates that disruption of TGF-β/Smad signaling pathway exist in human cervical cancer, suggesting that abnormal expressions of the member of TGF-β/Smad signaling pathway might contribute to the malignant progression of human cervical tumors via suppressing the tumor suppression function of TGF-β1 1's tumor suppression function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression and mutational analysis of TGF-β/Smads signaling in human cervical cancers

Tong

Huh

et al. 2009

J Gynecol Oncol

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“…In addition, it can induce apoptosis in gastric carcinoma cells (8), primary hepatocytes, hepatoma cells (9), and human lung epithelial cell lines (10). The mechanism of TGF-␤1-mediated apoptosis most likely varies among cell types, although caspase activation (11,12), up-regulation of p21 (13), and down-regulation of Bcl-x L expression (14) are commonly observed. However, TGF-␤1 induces apoptosis of retinal endothelial cells with decreased expression of p21 (15).…”

Section: Tgf-␤1 As An Enhancer Of Fas-mediated Apoptosis Of Lung Epitmentioning

confidence: 99%

TGF-β1 as an Enhancer of Fas-Mediated Apoptosis of Lung Epithelial Cells

Hagimoto

Kuwano

Inoshima

et al. 2002

The Journal of Immunology

187

106

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Transforming growth factor-β1 (TGF-β1) has important roles in lung fibrosis and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary fibrosis. In this study, we show that TGF-β1 induces apoptosis of primary cultured bronchiolar epithelial cells via caspase-3 activation and down-regulation of cyclin-dependent kinase inhibitor p21. Concentrations of TGF-β1 that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or rFas ligand-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble Fas ligand in the bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-β Ab. Otherwise, BALF from patients with hypersensitivity pneumonitis (HP) could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble Fas ligand. The concentrations of TGF-β1 in BALF from patients with IPF were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, coincubation with the low concentration of TGF-β1 and HP BALF created proapoptotic effects comparable with the IPF BALF. In vivo, the administration of TGF-β1 could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice. Our results demonstrate a novel role of TGF-β1 in the pathophysiology of pulmonary fibrosis as an enhancer of Fas-mediated apoptosis of lung epithelial cells.

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“…It has also been suggested that TGF-␤1 can induce apoptosis in human primary B lymphocytes (19 -21) and BL cell lines (20,(22)(23)(24)(25)(26). The induction of apoptosis by TGF-␤1 has also been observed in myeloid leukemia cells (27), gastric carcinoma cells (28), primary endometrial cells (29), primary hepatocytes and hepatoma cells (30), human cervical carcinoma cell lines (31), and human lung epithelial cell lines (32).…”

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confidence: 98%

Apoptosis Induced by TGF-β1 in Burkitt’s Lymphoma Cells Is Caspase 8 Dependent But Is Death Receptor Independent

Inman

Allday

2000

The Journal of Immunology

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TGF-β is a potent inducer of apoptosis in many Burkitt’s lymphoma (BL) cell lines. In this study, we characterize this apoptotic process in the EBV-negative BL41 cell line. Induction of apoptosis was detected as early as 8 h after TGF-β treatment, as assayed by TUNEL and poly(ADP-ribose) polymerase cleavage. FACS analysis demonstrates that this proceeds predominately from the G1, but also from the G2/M phases of the cell cycle. We observed no early detectable changes in the steady-state levels of Bcl-2 and several of its family members after TGF-β treatment. We detected cleavage of caspases 2, 3, 7, 8, and 9 into their active subunits. Consistent with the involvement of these enzymes in TGF-β-mediated apoptosis, the broad spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(Ome)-flouromethylketone (ZVAD-fmk) blocked TGF-β-induced apoptosis and revealed a G1 arrest in treated cells. Use of specific caspase inhibitors revealed that the induction of apoptosis is caspase 8 dependent, but caspase 3 independent. Activation of caspase 8 has been shown to be a critical event in death receptor-mediated apoptosis. However, TGF-β treatment of BL41 cells was found not to affect the cell surface expression of Fas, TNF-R1, DR3, DR4, or DR5, or the steady-state expression levels of Fas ligand, TNF-R1, DR3, DR4, and DR5. Furthermore, blocking experiments indicated that TGF-β-mediated apoptosis is not dependent on Fas ligand, TNF-α, tumor necrosis-like apoptosis-inducing ligand, or TNF-like weak inducer of apoptosis signaling. Therefore, it appears that TGF-β induces apoptosis in BL cell lines via caspase 8 in a death receptor-independent fashion.

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Transforming Growth Factor-β1 Induces Apoptosis through Down-Regulation of c-mycGene and Overexpression of p27Kip1Protein in Cervical Carcinoma

Cited by 34 publications

References 29 publications

Expression and mutational analysis of TGF-β/Smads signaling in human cervical cancers

Expression and mutational analysis of TGF-β/Smads signaling in human cervical cancers

TGF-β1 as an Enhancer of Fas-Mediated Apoptosis of Lung Epithelial Cells

Apoptosis Induced by TGF-β1 in Burkitt’s Lymphoma Cells Is Caspase 8 Dependent But Is Death Receptor Independent

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