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Blocking protein quality control to counter hereditary cancers

Publikation: Bidrag til tidsskriftReviewForskningpeer review

Harvard

Kampmeyer, C, Nielsen, SV, Clausen, L, Stein, A, Gerdes, A-M, Lindorff-Larsen, K & Hartmann-Petersen, R 2017, 'Blocking protein quality control to counter hereditary cancers' Genes Chromosomes and Cancer, bind 56, nr. 12, s. 823-831. https://doi.org/10.1002/gcc.22487

APA

Kampmeyer, C., Nielsen, S. V., Clausen, L., Stein, A., Gerdes, A-M., Lindorff-Larsen, K., & Hartmann-Petersen, R. (2017). Blocking protein quality control to counter hereditary cancers. Genes Chromosomes and Cancer, 56(12), 823-831. https://doi.org/10.1002/gcc.22487

CBE

Kampmeyer C, Nielsen SV, Clausen L, Stein A, Gerdes A-M, Lindorff-Larsen K, Hartmann-Petersen R. 2017. Blocking protein quality control to counter hereditary cancers. Genes Chromosomes and Cancer. 56(12):823-831. https://doi.org/10.1002/gcc.22487

MLA

Vancouver

Kampmeyer C, Nielsen SV, Clausen L, Stein A, Gerdes A-M, Lindorff-Larsen K o.a. Blocking protein quality control to counter hereditary cancers. Genes Chromosomes and Cancer. 2017 dec;56(12):823-831. https://doi.org/10.1002/gcc.22487

Author

Kampmeyer, Caroline ; Nielsen, Sofie V ; Clausen, Lene ; Stein, Amelie ; Gerdes, Anne-Marie ; Lindorff-Larsen, Kresten ; Hartmann-Petersen, Rasmus. / Blocking protein quality control to counter hereditary cancers. I: Genes Chromosomes and Cancer. 2017 ; Bind 56, Nr. 12. s. 823-831.

Bibtex

@article{98a4445328084193827837b5d139911a,
title = "Blocking protein quality control to counter hereditary cancers",
abstract = "Inhibitors of molecular chaperones and the ubiquitin-proteasome system have already been clinically implemented to counter certain cancers, including multiple myeloma and mantle cell lymphoma. The efficacy of this treatment relies on genomic alterations in cancer cells causing a proteostatic imbalance, which makes them more dependent on protein quality control (PQC) mechanisms than normal cells. Accordingly, blocking PQC, e.g. by proteasome inhibitors, may cause a lethal proteotoxic crisis in cancer cells, while leaving normal cells unaffected. Evidence, however, suggests that the PQC system operates by following a better-safe-than-sorry principle and is thus prone to target proteins that are only slightly structurally perturbed, but still functional. Accordingly, implementing PQC inhibitors may also, through an entirely different mechanism, hold potential for other cancers. Several inherited cancer susceptibility syndromes, such as Lynch syndrome and von Hippel-Lindau disease, are caused by missense mutations in tumor suppressor genes, and in some cases, the resulting amino acid substitutions in the encoded proteins cause the cellular PQC system to target them for degradation, although they may still retain function. As a consequence of this over-meticulous PQC mechanism, the cell may end up with an insufficient amount of the abnormal, but functional, protein, which in turn leads to a loss-of-function phenotype and manifestation of the disease. Increasing the amounts of such proteins by stabilizing with chemical chaperones, or by targeting molecular chaperones or the ubiquitin-proteasome system, may thus avert or delay the disease onset. Here, we review the potential of targeting the PQC system in hereditary cancer susceptibility syndromes.",
keywords = "Journal Article, Review",
author = "Caroline Kampmeyer and Nielsen, {Sofie V} and Lene Clausen and Amelie Stein and Anne-Marie Gerdes and Kresten Lindorff-Larsen and Rasmus Hartmann-Petersen",
note = "{\circledC} 2017 Wiley Periodicals, Inc.",
year = "2017",
month = "12",
doi = "10.1002/gcc.22487",
language = "English",
volume = "56",
pages = "823--831",
journal = "Genes Chromosomes and Cancer",
issn = "1045-2257",
publisher = "John/Wiley & Sons, Inc. John/Wiley & Sons Ltd",
number = "12",

}

RIS

TY - JOUR

T1 - Blocking protein quality control to counter hereditary cancers

AU - Kampmeyer, Caroline

AU - Nielsen, Sofie V

AU - Clausen, Lene

AU - Stein, Amelie

AU - Gerdes, Anne-Marie

AU - Lindorff-Larsen, Kresten

AU - Hartmann-Petersen, Rasmus

N1 - © 2017 Wiley Periodicals, Inc.

PY - 2017/12

Y1 - 2017/12

N2 - Inhibitors of molecular chaperones and the ubiquitin-proteasome system have already been clinically implemented to counter certain cancers, including multiple myeloma and mantle cell lymphoma. The efficacy of this treatment relies on genomic alterations in cancer cells causing a proteostatic imbalance, which makes them more dependent on protein quality control (PQC) mechanisms than normal cells. Accordingly, blocking PQC, e.g. by proteasome inhibitors, may cause a lethal proteotoxic crisis in cancer cells, while leaving normal cells unaffected. Evidence, however, suggests that the PQC system operates by following a better-safe-than-sorry principle and is thus prone to target proteins that are only slightly structurally perturbed, but still functional. Accordingly, implementing PQC inhibitors may also, through an entirely different mechanism, hold potential for other cancers. Several inherited cancer susceptibility syndromes, such as Lynch syndrome and von Hippel-Lindau disease, are caused by missense mutations in tumor suppressor genes, and in some cases, the resulting amino acid substitutions in the encoded proteins cause the cellular PQC system to target them for degradation, although they may still retain function. As a consequence of this over-meticulous PQC mechanism, the cell may end up with an insufficient amount of the abnormal, but functional, protein, which in turn leads to a loss-of-function phenotype and manifestation of the disease. Increasing the amounts of such proteins by stabilizing with chemical chaperones, or by targeting molecular chaperones or the ubiquitin-proteasome system, may thus avert or delay the disease onset. Here, we review the potential of targeting the PQC system in hereditary cancer susceptibility syndromes.

AB - Inhibitors of molecular chaperones and the ubiquitin-proteasome system have already been clinically implemented to counter certain cancers, including multiple myeloma and mantle cell lymphoma. The efficacy of this treatment relies on genomic alterations in cancer cells causing a proteostatic imbalance, which makes them more dependent on protein quality control (PQC) mechanisms than normal cells. Accordingly, blocking PQC, e.g. by proteasome inhibitors, may cause a lethal proteotoxic crisis in cancer cells, while leaving normal cells unaffected. Evidence, however, suggests that the PQC system operates by following a better-safe-than-sorry principle and is thus prone to target proteins that are only slightly structurally perturbed, but still functional. Accordingly, implementing PQC inhibitors may also, through an entirely different mechanism, hold potential for other cancers. Several inherited cancer susceptibility syndromes, such as Lynch syndrome and von Hippel-Lindau disease, are caused by missense mutations in tumor suppressor genes, and in some cases, the resulting amino acid substitutions in the encoded proteins cause the cellular PQC system to target them for degradation, although they may still retain function. As a consequence of this over-meticulous PQC mechanism, the cell may end up with an insufficient amount of the abnormal, but functional, protein, which in turn leads to a loss-of-function phenotype and manifestation of the disease. Increasing the amounts of such proteins by stabilizing with chemical chaperones, or by targeting molecular chaperones or the ubiquitin-proteasome system, may thus avert or delay the disease onset. Here, we review the potential of targeting the PQC system in hereditary cancer susceptibility syndromes.

KW - Journal Article

KW - Review

U2 - 10.1002/gcc.22487

DO - 10.1002/gcc.22487

M3 - Review

VL - 56

SP - 823

EP - 831

JO - Genes Chromosomes and Cancer

JF - Genes Chromosomes and Cancer

SN - 1045-2257

IS - 12

ER -

ID: 52408812