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Down-regulation of Thanatos-associated protein 11 by BCR-ABL promotes CML cell proliferation through c-Myc expression
- Source :
- International Journal of Cancer. 130:1046-1059
- Publication Year :
- 2011
- Publisher :
- Wiley, 2011.
-
Abstract
- Bcr-Abl activates various signaling pathways in chronic myelogenous leukemia (CML) cells. The proliferation of Bcr-Abl transformed cells is promoted by c-Myc through the activation of Akt, JAK2 and NF-κB. However, the mechanism by which c-Myc regulates CML cell proliferation is unclear. In our study, we investigated the role of Thanatos-associated protein 11 (THAP11), which inhibits c-Myc transcription, in CML cell lines and in hematopoietic progenitor cells derived from CML patients. The induction of THAP11 expression by Abl kinase inhibitors in CML cell lines and in CML-derived hematopoietic progenitor cells resulted in the suppression of c-Myc. In addition, over-expression of THAP11 inhibited CML cell proliferation. In colony forming cells derived from CML-aldehyde dehydrogenase (ALDH)(hi) /CD34(+) cells, treatment with Abl kinase inhibitors and siRNA depletion of Bcr-Abl induced THAP11 expression and reduced c-Myc expression, resulting in inhibited colony formation. Moreover, overexpression of THAP11 significantly decreased the colony numbers, and also inhibited the expression of c-myc target genes such as Cyclin D1, ODC and induced the expression of p21(Cip1) . The depletion of THAP11 inhibited JAK2 or STAT5 inactivation-mediated c-Myc reduction in ALDH(hi) /CD34(+) CML cells. Thus, the induced THAP11 might be one of transcriptional regulators of c-Myc expression in CML cell. Therefore, the induction of THAP11 has a potential possibility as a target for the inhibition of CML cell proliferation.
- Subjects :
- Male
Cancer Research
Cell
Fusion Proteins, bcr-abl
Genes, myc
Down-Regulation
HL-60 Cells
Piperazines
Cyclin D1
Cell Line, Tumor
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
hemic and lymphatic diseases
medicine
Humans
Protein Kinase Inhibitors
neoplasms
Protein kinase B
Cell Proliferation
ABL
Cell growth
Chemistry
Hematopoietic Stem Cells
medicine.disease
Cell biology
Repressor Proteins
Pyrimidines
medicine.anatomical_structure
Oncology
Cell culture
Benzamides
Imatinib Mesylate
Cancer research
Signal transduction
K562 Cells
Chronic myelogenous leukemia
Subjects
Details
- ISSN :
- 00207136
- Volume :
- 130
- Database :
- OpenAIRE
- Journal :
- International Journal of Cancer
- Accession number :
- edsair.doi.dedup.....900a633eb9183ee512056809f3bf9ade