Regulation of HTERT by BCR-ABL at Multiple Levels in K562 Cells

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2011 Dec 14

PMID 22151181

Citations 13

Authors

Juin Hsien Chai

Yong Zhang

Wei Han Tan

Wee Joo Chng

Baojie Li

Xueying Wang

Affiliations

Soon will be listed here.

Abstract

Background: The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at multiple levels in K562 cells.

Methods: Molecular techniques such as over expression, knockdown, real-time PCR, immunoprecipitation, western blotting, reporter assay, confocal microscopy, telomerase assays and microarray were used to suggest that hTERT expression and activity is modulated by BCR-ABL at multiple levels.

Results: Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL negative cells). We also demonstrated that the transcription factor STAT5a plays a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and hTERT protein level in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec.

Conclusions: Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients.

Citing Articles

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The regulations of telomerase reverse transcriptase (TERT) in cancer.

Liu M, Zhang Y, Jian Y, Gu L, Zhang D, Zhou H Cell Death Dis. 2024; 15(1):90.

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Mechanism of Human Telomerase Reverse Transcriptase () Regulation and Clinical Impacts in Leukemia.

Yik M, Azlan A, Rajasegaran Y, Rosli A, Mohd Yusoff N, Moses E Genes (Basel). 2021; 12(8).

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