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1. Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1.

Author

Soliera AR, Mariani SA, Audia A, Lidonnici MR, Addya S, Ferrari-Amorotti G, Cattelani S, Manzotti G, Fragliasso V, Peterson L, Perini G, Holyoake TL, and Calabretta B

Subjects
Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Blotting, Western, Chromatin Immunoprecipitation, Colony-Forming Units Assay, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, Down-Regulation, Gene Expression Profiling, Humans, Immunoenzyme Techniques, Indoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Luciferases metabolism, Myeloid Cell Leukemia Sequence 1 Protein, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 metabolism, Pyrroles pharmacology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, STAT5 Transcription Factor antagonists & inhibitors, STAT5 Transcription Factor metabolism, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Tumor Cells, Cultured, Cell Proliferation, DNA-Binding Proteins metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Proto-Oncogene Proteins c-bcl-2 genetics, STAT5 Transcription Factor genetics, Transcription Factors metabolism
Abstract

Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein. STAT 5B and Mcl-1, two genes important for the proliferation and survival of hematopoietic stem cells, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34+ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34+ CML cells.

Published
2012
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2. Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate.

Author

Bryant KG, Camacho J, Jasmin JF, Wang C, Addya S, Casimiro MC, Fortina P, Balasubramaniam S, Knudsen KE, Schwarting R, Lisanti MP, and Mercier I

Subjects
Animals, Caveolin 1 genetics, Cell Cycle Proteins metabolism, Cell Nucleus metabolism, DNA-Binding Proteins metabolism, Epithelium metabolism, Female, Gene Expression Profiling, Genes, Neoplasm, Male, Mice, Mice, Transgenic, Minichromosome Maintenance Complex Component 7, Nuclear Proteins metabolism, Orchiectomy, Organ Size, Phosphorylation, Prostate cytology, Protein Transport, Proteome genetics, Proteome metabolism, Receptors, Androgen genetics, Receptors, Androgen metabolism, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Testosterone physiology, Transcriptional Activation, Caveolin 1 metabolism, Cell Proliferation, Gene Expression, Prostate growth & development, Testosterone pharmacology
Abstract

Prostate cancer (PCa) continues to be one of the leading causes of cancer-related deaths among American men. The prostate relies upon the androgen receptor (AR) to mediate the effects of androgens on normal growth, a reliance that is maintained during malignant prostate growth. Caveolin-1 (Cav-1), the main structural component of caveolae, has been shown to promote the malignant growth and invasion of prostate tumors. In vitro work has shown that Cav-1 can act as an AR coactivator by enhancing its transciptional activity. However, it is unknown how Cav-1 affects androgen-dependent growth and signaling in vivo. To explore this role, a novel mouse model of Cav-1 overexpression was developed with a hormone-insensitive promoter. Cav-1 transgenic (Tg) mice subjected to castration and androgen stimulation display enlarged prostate weights and increased DNA synthesis. Through gene transcript and proteomic profiling, we demonstrate that Cav-1 overexpression favors androgen-regulated responses and enhances processes involved in transcription, cell cycle progression and protein synthesis. Interestingly, Cav-1 overexpression was associated with an increase in the phosphorylation of AR on serine 210, a post-translational modification linked to its activity under androgen-stimulated conditions. In addition, these mice exhibited an increase in the phosphorylation of ribosomal S6 protein on serine 235/236 (pS6), a marker of protein synthesis and a downstream component of the mTOR pathway. Thus, Cav-1 Tg mice could serve as a novel model for studying AR-regulated pathways involved in prostate growth and proliferation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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3. Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1

Author

Maria Rosa Lidonnici, Tessa L. Holyoake, Giovanni Perini, Samanta A. Mariani, Gloria Manzotti, Valentina Fragliasso, Bruno Calabretta, Giovanna Ferrari-Amorotti, Alessandra Audia, Sara Cattelani, Angela Rachele Soliera, Sankar Addya, Luke F. Peterson, Soliera A.R., Mariani S.A., Audia A, Lidonnici M.R., Addya S., Ferrari-Amorotti G., Cattelani S., Manzotti G., Fragliasso V., Peterson L., Perini G., Holyoake T.L., and Calabretta B.

Subjects
Cancer Research, P210BCR/ABL, Indoles, CD34, Immunoenzyme Techniques, oncogene, hemic and lymphatic diseases, STAT5 Transcription Factor, Tumor Cells, Cultured, cell survival, tumor suppressor gene, therapy, Luciferases, STAT4, Oligonucleotide Array Sequence Analysis, ABL, Reverse Transcriptase Polymerase Chain Reaction, Hematology, Cell biology, DNA-Binding Proteins, Haematopoiesis, Oncology, Proto-Oncogene Proteins c-bcl-2, Stem cell, Chromatin Immunoprecipitation, Blotting, Western, Down-Regulation, Biology, Real-Time Polymerase Chain Reaction, Colony-Forming Units Assay, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Biomarkers, Tumor, Humans, Pyrroles, RNA, Messenger, HEMATOPOIETIC STEM CELLS, Cell Proliferation, Gene Expression Profiling, medicine.disease, Molecular biology, GFI-1, STAT5B, Myeloid Cell Leukemia Sequence 1 Protein, Ectopic expression, MCL-1, Chronic myelogenous leukemia, K562 cells, Transcription Factors
Abstract

Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein. STAT 5B and Mcl-1, two genes important for the proliferation and survival of hematopoietic stem cells, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34+ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34+ CML cells.

Published
2012

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