Mol Cell：NCI科学家发现分子伴侣Hsp90的分子开关
Other Designations: heat shock 90kD protein 1, alpha; heat shock 90kD protein 1, alpha-like 4; heat shock 90kD protein, alpha-like 4; heat shock 90kDa protein 1, alpha
Chromosome: 14; Location: 14q32.33
MIM: 140571
GeneID: 3320
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Latest Paper:
Mol Cell. 2007 Jan 12;25 (1):151-9 17218278
An acetylation site in the middle domain of hsp90 regulates chaperone function.
Bradley T Scroggins , Kenneth Robzyk , Dongxia Wang , Monica G Marcu , Shinji Tsutsumi , Kristin Beebe , Robert J Cotter , Sara Felts , David Toft , Larry Karnitz , Neal Rosen , Len Neckers
Heat-shock protein 90 (Hsp90) chaperones a key subset of signaling proteins and is necessary for malignant transformation. Hsp90 is subject to an array of posttranslational modifications that affect its function, including acetylation. Histone deacetylase (HDAC) inhibitors and knockdown of HDAC6 induce Hsp90 acetylation and inhibit its activity. However, direct determination of the functional consequences of Hsp90 acetylation has awaited mapping of specific sites. We now demonstrate that Hsp90 K294 is acetylated. Mutational analysis of K294 shows that its acetylation status is a strong determinant of client protein and cochaperone binding. In yeast, Hsp90 mutants that cannot be acetylated at K294 have reduced viability and chaperone function compared to WT or to mutants that mimic constitutive acetylation. These data suggest that acetylation/deacetylation of K294 plays an important role in regulating the Hsp90 chaperone cycle.
Br J Cancer. 2007 Jan 9; : 17211469
HIF and fumarate hydratase in renal cancer.
Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are predisposed to the development of leiomyomas of the skin and uterus. In addition, this clinical entity also can result in the development of biologically aggressive kidney cancer. Affected individuals harbour a germline mutation of the fumarate hydratase (FH) gene, which encodes an enzyme that catalyses conversion of fumarate to malate in the Kreb's cycle. Thus far, proposed mechanisms for carcinogeneis associated with this syndrome include aberrant apoptosis, oxidative stress, and pseudohypoxic drive. At this time, the majority of accumulating data support a role for pseudohypoxic drive in tumour development. The link between FH mutation and pseudohypoxic drive may reside in the biochemical alterations resulting from diminished/absent FH activity. These biochemical derangements may interfere with oxygen homeostasis and result in a cellular environment conducive to tumour formation.British Journal of Cancer advance online publication, 9 January 2007; doi:10.1038/sj.bjc.6603547 www.bjcancer.com.
ACS Chem Biol. 2006 Jun 20;1(5):279-84 17163756
Tumor selectivity of hsp90 inhibitors: the explanation remains elusive.
Len Neckers , Gabriela Chiosis
ABSTRACT Two recent papers attempt to solve both the tumor selectivity and the in vivo tumor accumulation profiles seen with some Hsp90 inhibitors. They spotlight the higher affinity of ansamycins' hydroquinone over the quinone form for Hsp90 and further discuss its possible contribution to ansamycins' tumor selectivity.
J Am Chem Soc. 2006 Dec 6;128(48):15529-15536 17132020
Novobiocin: Redesigning a DNA Gyrase Inhibitor for Selective Inhibition of Hsp90.
[My paper] Joseph Burlison , Len Neckers , Andrew Smith , Anthony Maxwell , Brian Blagg
Novobiocin is a member of the coumermycin family of antibiotics and is a well-established inhibitor of DNA gyrase. Recent studies have shown that novobiocin binds to a previously unrecognized ATP-binding site at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at approximately 700 &mgr;M. In an effort to develop more efficacious inhibitors of the C-terminal binding site, a library of novobiocin analogues was prepared and initial structure-activity relationships revealed. These data suggested that the 4-hydroxy moiety of the coumarin ring and the 3'-carbamate of the noviose appendage were detrimental to Hsp90 inhibitory activity. In an effort to confirm these findings, 4-deshydroxy novobiocin (DHN1) and 3'-descarbamoyl-4-deshydroxynovobiocin (DHN2) were prepared and evaluated against Hsp90. Both compounds were significantly more potent than the natural product, and DHN2 proved to be more active than DHN1. In an effort to determine whether these moieties are important for DNA gyrase inhibition, these compounds were tested for their ability to inhibit DNA gyrase and found to exhibit significant reduction in gyrase activity. Thus, we have established the first set of compounds that clearly differentiate between the C-terminus of Hsp90 and DNA gyrase, converted a well-established gyrase inhibito
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