Abstract
Activation of Ras or Raf in the human medullary thyroid carcinoma (MTC) cell line, TT, induces growth arrest and differentiation via two parallel, yet independent, pathways. One of these pathways is intracellular and the other is a cell-extrinsic, autocrine/paracrine pathway mediated by the leukemia inhibitory factor (LIF)/JAK/STAT pathway. Here, we show that IFI16 is a necessary and sufficient downstream effector for LIF effects in MTC cells, specifically required for the LIF/JAK/STAT pathway-induced growth inhibition in these cells. IFI16 was induced by Raf or LIF. Dominant-negative STAT3 could block the induction, indicating that Raf can induce IFI16 only via the cell-extrinsic pathway. Knock-down of IFI16 using siRNA abrogated LIF-induced changes in cellular levels of E2F1, cyclin D1, and p21WAF/CIP1, and cell cycle arrest. In addition, adenovirus-mediated overexpression of IFI16 was sufficient to induce growth arrest. In contrast to its essential role for LIF-mediated growth arrest, IFI16 was not required for differentiation induced by LIF. Knock-down of IFI16 could not block changes in differentiation markers of the MTC cells, including calcitonin, RET, and cell morphology. Our study identifies IFI16 as an essential growth-specific effector of the cell-extrinsic growth inhibitory pathway of Ras/Raf signaling in MTC cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics
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Calcitonin / metabolism
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Carcinoma, Medullary / pathology
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Cell Cycle
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Cell Cycle Proteins / metabolism
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Cell Differentiation
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Cell Line
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Cell Line, Tumor
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Cell Proliferation
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Culture Media / pharmacology
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Culture Media, Conditioned
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins / metabolism
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E2F Transcription Factors
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E2F1 Transcription Factor
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Genes, Dominant
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Humans
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Immunoblotting
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Interleukin-6 / metabolism*
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Janus Kinase 1
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Leukemia Inhibitory Factor
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Models, Biological
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Oligonucleotide Array Sequence Analysis
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Phosphoproteins / metabolism
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Phosphoproteins / physiology*
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Plasmids / metabolism
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Protein-Tyrosine Kinases / metabolism*
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RNA, Small Interfering / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor
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Thyroid Neoplasms / metabolism*
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Time Factors
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Trans-Activators / metabolism*
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Transcription Factors / metabolism
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Transfection
Substances
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CDKN1A protein, human
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Cell Cycle Proteins
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Culture Media
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Culture Media, Conditioned
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F1 protein, human
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Interleukin-6
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LIF protein, human
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Leukemia Inhibitory Factor
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Nuclear Proteins
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Phosphoproteins
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RNA, Small Interfering
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Transcription Factors
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Cyclin D1
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IFI16 protein, human
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Calcitonin
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Protein-Tyrosine Kinases
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JAK1 protein, human
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Janus Kinase 1