Journal article
Rearrangement of Upstream Sequences of the hTERT Gene During Cellular Immortalization
Genes chromosomes & cancer, Vol.48(11), pp.963-974
11/2009
Handle:
https://hdl.handle.net/2376/104758
PMCID: PMC2889911
PMID: 19672873
Abstract
Telomerase expression, resulting from transcriptional activation of the
hTERT
gene, allows cells to acquire indefinite proliferative potential during cellular immortalization and tumorigenesis. However, mechanisms of
hTERT
gene activation in many immortal cell lines and cancer cells are poorly understood. Here, we report our studies on hTERT activation using genetically related pairs of telomerase-negative (Tel
−
) and -positive (Tel
+
) fibroblast lines. First, whereas transiently transfected plasmid reporters did not recapitulate the endogenous hTERT promoter, the promoter in chromosomally integrated bacterial artificial chromosome (BAC) reporters was activated in a subset of Tel
+
cells, indicating that activation of the hTERT promoter required native chromatin context and/or distal regulatory elements. Second, the
hTERT
gene, located near the telomere of chromosome 5p, was translocated in all three Tel
+
cell lines but not in their parental pre-crisis cells and Tel
−
immortal siblings. The breakage points were mapped to regions upstream of the hTERT promoter, indicating that the
hTERT
gene was the target of these chromosomal rearrangements. In two Tel
+
cell lines, translocation of the endogenous
hTERT
gene appeared to be the major mechanism of its activation as the activity of hTERT promoter in many chromosomally integrated BAC reporters, with intact upstream and downstream neighboring loci, remained relatively low. Therefore, our results suggest that rearrangement of upstream sequences is an important new mechanism of hTERT promoter activation during cellular immortalization. The chromosomal rearrangements likely occurred during cellular crisis and facilitated by telomere dysfunction. Such translocations allowed the hTERT promoter to escape from the native condensed chromatin environment.
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Details
- Title
- Rearrangement of Upstream Sequences of the hTERT Gene During Cellular Immortalization
- Creators
- Yuanjun Zhao - Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PAShuwen Wang - Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PAEvgenya Y Popova - Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PASergei A Grigoryev - Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PAJiyue Zhu - Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA
- Publication Details
- Genes chromosomes & cancer, Vol.48(11), pp.963-974
- Academic Unit
- Pharmaceutical Sciences, Department of
- Identifiers
- 99900546519801842
- Language
- English
- Resource Type
- Journal article