Interferon-β induces S phase slowing via up-regulated expression of PML in squamous carcinoma cells

Vannucchi, Serena; Percario, Zulema Antonia; Chiantore, Maria Vincenza; Matarrese, Paola; Chelbi-Alix, Mounira K.; Fagioli, Marta; Pelicci, Pier Giuseppe; Malorni, Walter; Fiorucci, Gianna; Romeo, Giovanna; Affabris, Elisabetta

doi:10.1038/sj.onc.1203883

Cited by 25 publications

(26 citation statements)

References 56 publications

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“…More recently, we demonstrated that IFN-b affects cell growth of SCC lines by inducing a significant lengthening of the cell cycle S-phase (Vannucchi et al, 2000). In the present study, we define the mechanisms of IFN-negative control of cell growth in ME-180 SCC cells.…”

Section: Introductionmentioning

confidence: 91%

TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-β in cervical carcinoma cells

et al. 2005

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Interferon (IFN)-b induces S-phase slowing and apoptosis in human papilloma virus (HPV)-positive cervical carcinoma cell line ME-180. Here, we show that apoptosis is a consequence of the S-phase lengthening imposed by IFNb, demonstrating the functional correlation between Sphase alteration and apoptosis induction. In ME-180 cells, where p53 function is inhibited by HPV E6 oncoprotein, IFN-b effects on cell cycle and apoptosis occur independently of p53. The apoptosis due to IFN-b is mediated by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a manner dependent on the S-phase deregulation. IFN-b appears to increase TRAIL expression both directly at the mRNA level and indirectly by augmenting surface protein levels as a consequence of the induced S-phase cell accumulation. Moreover, the alteration of the S-phase due to IFN-b promotes TRAILdependent apoptosis by potentiating cell sensitivity to TRAIL, possibly through induction of a proapoptotic NFjB activity and TRAIL-R2 receptor expression. Interestingly, IFN-b-induced TRAIL-dependent apoptotic events strongly differ in the requirement of caspase activity. These results show that IFN-b may induce an apoptotic response by deregulating cell cycle. Understanding the linkage between these mechanisms appears to be of primary importance in the search for new IFN-based therapeutic strategies to circumvent cancer disease or improve clinical outcome.

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Section: Introductionmentioning

confidence: 91%

TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-β in cervical carcinoma cells

et al. 2005

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“…This stimulates a pleiotropy of biological responses, of which antiviral activity is the most studied. In addition, interferon induces a strong antiproliferative response in many cell lines, which is a combination of cell cycle arrest (particularly S-phase arrest [47,48]) and initiation of apoptosis (49). To activate interferon-induced apoptosis, an intact JAK-STAT pathway is required (50).…”

Section: Discussionmentioning

confidence: 99%

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Apelbaum

Yarden

Warszawski

et al. 2013

Molecular and Cellular Biology

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Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-␥) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.

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“…However, the roles of other genes such as decorin and interferon-␤ are controversial because they were reported to suppress tumor growth. 29,30 In addition, the functions of RNF11, foocen, and TB2-like 1 genes belonging to type I group are currently unknown. 31,32 On the other hand, we identified eight genes suppressed by both RET-MEN2A and RET-MEN2B mutant proteins (type IV genes).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

Watanabe¹,

Ichihara²,

Hashimoto³

et al. 2002

The American Journal of Pathology

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Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A-and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-␣6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype. The RET proto-oncogene encodes a receptor tyrosine kinase with a cadherin-related motif and a cysteine-rich domain in the extracellular domain and is located on chromosome 10q11.2.1,2 It has been demonstrated that RET is a functional receptor for four related neurotrophic factors including glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin. These factors are known to require glycosylphosphatidylinositol-anchored co-receptors, GFR-␣s, as ligand-binding components and to promote the survival of various central and peripheral neurons in culture.1,2 In addition, gene knockout studies revealed that the GDNF/RET signaling plays a crucial role in the development of the enteric nervous system and the kidney. [3][4][5][6] Germline mutations of the RET gene cause dominant inherited cancer syndromes; multiple endocrine neoplasia (MEN) type 2A and 2B.7-10 MEN 2A is characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia. MEN 2B shows a more complex phenotype with association of MTC, pheochromocytoma, and developmental abnormalities such as mucosal neuroma, hyperganglionosis of the intestinal tract, and marfanoid skeletal changes. The MEN2A mutations were identified in cysteine residues of the RET extracellular domain, leading to ligand-independent RET dimerization. 11,12 The MEN2B mutations were detected in methionine at codon 918 or in alanine at codon 883 in the tyrosine kinase domain and appear to activate RET without dimerization. 12,13 A variety of si...

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Interferon-β induces S phase slowing via up-regulated expression of PML in squamous carcinoma cells

Cited by 25 publications

References 56 publications

TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-β in cervical carcinoma cells

TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-β in cervical carcinoma cells

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

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