Alternative splicing of human telomerase reverse transcriptase may not be involved in telomerase regulation during all-trans-retinoic acid-induced HL-60 cell differentiation.
Alternative splicing of the human telomerase reverse transcriptase subunit (hTERT) suppresses telomerase activity during the development of human fetal kidney cells into mature cells. Tumor cell differentiation is the process of turning abnormal tumor cells into 'normal' cells accompanied by down-regulation of telomerase activity. However, the precise mechanism of the regulation of telomerase activity in differentiated cells is not fully understood. In this study, we observed the role of alternative splicing of hTERT in the regulation of telomerase activity in all-trans-retinoic acid (ATRA)-induced, differentiated HL-60 cells. ATRA-induced down-regulation of telomerase activity in differentiated HL-60 cells was associated with a decrease in hTERT and an increase in human telomerase-associated protein-1 (hTP1) transcription. Expression of full length variant hTERT alpha+ beta+ mRNA decreased in a dose- and time-dependent manner. The drop of hTERT beta- mRNA was time-dependent. hTERT alpha- and hTERT alpha- beta- mRNA were reduced dramatically after ATRA treatment. In the dose-effect study, hTERT alpha+ beta+ and hTERT beta- maintained a relatively stable ratio when telomerase activity decreased largely from treatment with 1 to 5 microM ATRA. Although the splicing pattern of hTERT mRNA was altered in time-effect research, the change was not related to the ATRA-treated decline of telomerase activity. The expression of alternative splicing variants of hTERT also decreased at the protein level. All these results suggested that alternative splicing of hTERT mRNA may not contribute to the suppression of telomerase activity during ATRA-induced HL-60 leukemia cell differentiation.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Wei-Jun
WJ
Liu
Yong-Wei
YW
Zhang
Zhi-Xiang
ZX
Zhang
Jian
J
Ding
D017398:Alternative Splicing / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D019098:Telomerase / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D014212:Tretinoin; D019098:Telomerase