Curcumin inhibits nuclear localization of telomerase by dissociating the Hsp90 co-chaperone p23 from hTERT

Lee, Ji Hoon; Chung, In Kwon

doi:10.1016/j.canlet.2009.08.026

Cited by 73 publications

(52 citation statements)

References 35 publications

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“…Multichaperone complexes containing Hsp90, Hsp70, and other co-chaperones have been shown to assemble on substrate polypeptides through several intermediate assembly steps (51). Prior studies indicated that Hsp90 and p23 interact with hTERT and are required for the assembly of active telomerase (18,27) and the nuclear localization of hTERT (42). Hsp70 also associates with hTERT but readily dissociates when telomerase is folded into its active form.…”

Section: Discussionmentioning

confidence: 99%

“…Because Hsp90 and p23 remain associated with active telomerase in the nucleus (27,42), we wanted to verify the critical role of p23 in the regulation of telomerase activity. To determine the effect of p23 knockdown on hTERT degradation, H1299 cells were transfected with hTERT-HA and siRNA duplexes targeting p23 (sip23-1 and sip23-2), and we assessed the protein levels.…”

Section: Chip Remodels the Htert-chaperone Complex To Inactive Form-thementioning

confidence: 99%

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CHIP Promotes Human Telomerase Reverse Transcriptase Degradation and Negatively Regulates Telomerase Activity

Lee

Khadka

Baek

et al. 2010

Journal of Biological Chemistry

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The maintenance of eukaryotic telomeres requires telomerase, which is minimally composed of a telomerase reverse transcriptase (TERT) and an associated RNA component. Telomerase activity is tightly regulated by expression of human (h) TERT at both the transcriptional and post-translational levels. The Hsp90 and p23 molecular chaperones have been shown to associate with hTERT for the assembly of active telomerase. Here, we show that CHIP (C terminus of Hsc70-interacting protein) physically associates with hTERT in the cytoplasm and regulates the cellular abundance of hTERT through a ubiquitin-mediated degradation. Overexpression of CHIP prevents nuclear translocation of hTERT and promotes hTERT degradation in the cytoplasm, thereby inhibiting telomerase activity. In contrast, knockdown of endogenous CHIP results in the stabilization of cytoplasmic hTERT. However, it does not affect the level of nuclear hTERT and has no effect on telomerase activity and telomere length. We further show that the binding of CHIP and Hsp70 to hTERT inhibits nuclear translocation of hTERT by dissociating p23. However, Hsp90 binding to hTERT was not affected by CHIP overexpression. These results suggest that CHIP can remodel the hTERTchaperone complexes. Finally, the amount of hTERT associated with CHIP peaks in G 2 /M phases but decreases during S phase, suggesting a cell cycle-dependent regulation of hTERT. Our data suggest that CHIP represents a new pathway for modulating telomerase activity in cancer.Telomeres, the specialized nucleoprotein complexes at the ends of eukaryotic chromosomes, are essential for the maintenance of chromosome integrity (1, 2). In most organisms, telomere DNA consists of long tracts of duplex telomere repeats (TTAGGG in vertebrates) with 3Ј single-stranded G overhangs (3) and is tightly associated with the six-protein complex, shelterin, which protects chromosome termini from being recognized as sites of DNA damage (4, 5). Loss of telomere function results in chromosome end fusions, degradation, and other inappropriate reactions, leading to cell senescence, apoptosis, or abnormal cell proliferation (6, 7). In the absence of a telomere maintenance pathway, dividing somatic cells show a progressive loss of telomeric DNA during successive rounds of cell division because of a DNA end replication problem (8, 9). Thus, telomere shortening functions as a control mechanism that regulates the proliferative capacity of cells. Although recombination-mediated telomere elongation has been demonstrated for replenishing telomere DNA (10, 11), the major mechanism to offset telomere erosion is based on telomerase (12, 13). In humans, telomerase is strongly repressed in normal somatic tissues but is expressed in most cancer cells, suggesting that the activation of telomerase is a critical step in human oncogenesis (14,15).Although the enzymatic activity of telomerase is regulated by hTERT 2 at the transcriptional level (16, 17), several lines of evidence have suggested a post-translational regulation of telomerase activity....

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Section: Discussionmentioning

confidence: 99%

Section: Chip Remodels the Htert-chaperone Complex To Inactive Form-thementioning

confidence: 99%

CHIP Promotes Human Telomerase Reverse Transcriptase Degradation and Negatively Regulates Telomerase Activity

Lee

Khadka

Baek

et al. 2010

Journal of Biological Chemistry

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“…Jung et al [207] observed that curcumin induced degradation of a Hsp90 client namely ErbB2. Lee et al [208] reported the curcumin induced dissociation of the Hsp90/p23complex from hTERT. Giommarelli et al [209] observed that curcumin facilitates the dissociation of client proteins including EGFR, Akt, survivin and Raf-1 from Hsp90 complexes.…”

Section: Curcuminmentioning

confidence: 99%

Hsp90: Friends, clients and natural foes

et al. 2016

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“…Tumor cells typically maintain telomere length by activation of the telomerase subunit hTERT. It was demonstrated that both the expression and nuclear translocation of hTERT is inhibited by curcumin in H1299 human non-small cell lung carcinoma cells (Lee and Chung, 2010), which could lead to telomere shortening and activation of p53 and p16…”

Section: The Production Of P27mentioning

confidence: 99%

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Golen²,

et al. 2013

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Curcumin inhibits nuclear localization of telomerase by dissociating the Hsp90 co-chaperone p23 from hTERT

Cited by 73 publications

References 35 publications

CHIP Promotes Human Telomerase Reverse Transcriptase Degradation and Negatively Regulates Telomerase Activity

CHIP Promotes Human Telomerase Reverse Transcriptase Degradation and Negatively Regulates Telomerase Activity

Hsp90: Friends, clients and natural foes

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

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