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PMID:19567472

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Citation

Oh, W, Ghim, J, Lee, EW, Yang, MR, Kim, ET, Ahn, JH and Song, J (2009) PML-IV functions as a negative regulator of telomerase by interacting with TERT. J. Cell. Sci. 122:2613-22

Abstract

Maintaining proper telomere length requires the presence of the telomerase enzyme. Here we show that telomerase reverse transcriptase (TERT), a catalytic component of telomerase, is recruited to promyelocytic leukemia (PML) nuclear bodies through its interaction with PML-IV. Treatment of interferon-alpha (IFNalpha) in H1299 cells resulted in the increase of PML proteins with a concurrent decrease of telomerase activity, as previously reported. PML depletion, however, stimulated telomerase activity that had been inhibited by IFNalpha with no changes in TERT mRNA levels. Upon treatment with IFNalpha, exogenous TERT localized to PML nuclear bodies and binding between TERT and PML increased. Immunoprecipitation and immunofluorescence analyses showed that TERT specifically bound to PML-IV. Residues 553-633 of the C-terminal region of PML-IV were required for its interaction with the TERT region spanning residues 1-350 and 595-946. The expression of PML-IV and its deletion mutant, 553-633, suppressed intrinsic telomerase activity in H1299. TERT-mediated immunoprecipitation of PML or the 553-633 fragment demonstrated that these interactions inhibited telomerase activity. H1299 cell lines stably expressing PML-IV displayed decreased telomerase activity with no change of TERT mRNA levels. Accordingly, telomere length of PML-IV stable cell lines was shortened. These results indicate that PML-IV is a negative regulator of telomerase in the post-translational state.

Links

PubMed Online version:10.1242/jcs.048066

Keywords

Down-Regulation; Fibroblasts/metabolism; Fluorescent Antibody Technique; Humans; Immunoblotting; Immunoenzyme Techniques; Immunoprecipitation; Interferon-alpha/pharmacology; Liver Neoplasms/metabolism; Liver Neoplasms/pathology; Lung Neoplasms/metabolism; Lung Neoplasms/pathology; Nuclear Proteins/physiology; RNA, Messenger/metabolism; Telomerase/genetics; Telomerase/metabolism; Telomere/metabolism; Transcription Factors/physiology; Tumor Cells, Cultured; Tumor Suppressor Proteins/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TERT

located_in

GO:0005654: nucleoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TERT

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P29590-5

F

Seeded From UniProt

complete

ADE05:E1B55

involved_in

GO:0032211: negative regulation of telomere maintenance via telomerase

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

ADE05:E1B55

involved_in

GO:0051974: negative regulation of telomerase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

ADE05:E1B55

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14746

F

Seeded From UniProt

complete

HUMAN:TERT

colocalizes_with

GO:0016605: PML body

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TERT

part_of

GO:0005654: nucleoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PML

involved_in

GO:0032211: negative regulation of telomere maintenance via telomerase

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PML

involved_in

GO:0051974: negative regulation of telomerase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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