P504s

Jiang, Zhong; Woda, Bruce A.; Rock, Kenneth L.; Xu, Yingdan; Savas, Louis; Khan, Ashraf; Pihán, Germán; Cai, Feng; Babcook, John S.; Rathanaswami, Palaniswami; Reed, Steven G.; Xu, Jiangchun; Fanger, Gary R.

doi:10.1097/00000478-200111000-00007

Cited by 326 publications

(57 citation statements)

References 17 publications

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“…AMACR has recently been shown overexpressed in prostate cancers at both the transcript level by microarray experiments and at the protein level (Xu et al, 2000;Luo et al, 2002;Rubin et al, 2002). Further studies by immunohistochemistry have demonstrated the elevation of AMACR protein in more than 90% of prostate cancer cases but not in benign prostatic tissues, suggesting that AMACR may be a more specific marker than prostate-specific antigen (PSA) for prostate cancer (Jiang et al, 2001;Luo et al, 2002;Rubin et al, 2002). This gene has never been associated with any subtype of RCC.…”

Section: Discussionmentioning

confidence: 99%

Molecular subclassification of kidney tumors and the discovery of new diagnostic markers

et al. 2003

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We analysed the expression profiles of 70 kidney tumors of different histological subtypes to determine if these subgroups can be distinguished by their gene expression profiles, and to gain insights into the molecular mechanisms underlying each subtype. In all, 39 clear cell renal cell carcinomas (RCC), seven primary and one metastatic papillary RCC, six granular RCC from old classification, five chromophobe RCC, five sarcomatoid RCC, two oncocytomas, three transitional cell carcinomas (TCC) of the renal pelvis and five Wilms' tumors were compared with noncancerous kidney tissues using microarrays containing 19 968 cDNAs. Based on global gene clustering of 3560 selected cDNAs, we found distinct molecular signatures in clear cell, papillary, chromophobe RCC/ oncocytoma, TCC and Wilms' subtypes. The close clustering in each of these subtypes points to different tumorigenic pathways as reflected by their histological characteristics. In the clear cell RCC clustering, two subgroups emerged that correlated with clinical outcomes, confirming the potential use of gene expression signatures as a predictor of survival. In the so-called granular cell RCC (terminology for a subtype that is no longer preferred), none of the six cases clusters together, supporting the current view that they do not represent a single entity. Blinded histological re-evaluation of four cases of 'granular RCC' led to their reassignment to other existing histological subtypes, each compatible with our molecular classification. Finally, we found gene sets specific to each subtype. In order to establish the use of some of these genes as novel subtype markers, we selected four genes and performed immunohistochemical analysis on 40 cases of primary kidney tumors. The results were consistent with the gene expression microarray data: glutathione S-transferase a was highly expressed in clear cell RCC, a methylacyl racemase in papillary RCC, carbonic anhydrase II in chromophobe RCC and K19 in TCC. In conclusion, we demonstrated that molecular profiles of kidney cancers closely correlated with their histological subtypes. We have also identified in these subtypes differentially expressed genes that could have important diagnostic and therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Molecular subclassification of kidney tumors and the discovery of new diagnostic markers

et al. 2003

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“…In spite of the availability of biomarkers for PCA, the basic molecular mechanisms regulating its development and progression are still very poorly understood (Nupponen and Visakorpi, 1999;Jiang et al, 2001;Kuefer et al, 2002;Rubin et al, 2002;Varambally et al, 2002;Yang et al, 2002). Recognition of the precursor lesions of PCA has become a primary focus in recent years.…”

Section: Introductionmentioning

confidence: 99%

Detection and expression of human BK virus sequences in neoplastic prostate tissues

2004

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“…Using a knock-out mouse strain, it could be shown that Amacr is essential for detoxification of alimentary phytol, whereas alternative minor pathways for generation of bile acids suffice for survival of Amacr-deficient individuals (12). Elevated levels of Amacr have been found to correlate with human prostate cancer (13,14), kidney tumors (15), and colon carcinomas (16).…”

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α-Methylacyl-CoA Racemase from Mycobacterium tuberculosis

Savolainen

Bhaumik

Schmitz

et al. 2005

Journal of Biological Chemistry

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␣-Methylacyl-CoA racemase (Amacr) catalyzes the racemization of ␣-methyl-branched CoA esters. Sequence comparisons have shown that this enzyme is a member of the family III CoA transferases. The mammalian Amacr is involved in bile acid synthesis and branched-chain fatty acid degradation. In human, mutated variants of Amacr have been shown to be associated with disease states. Amino acid sequence alignment of Amacrs and its homologues from various species revealed 26 conserved protic residues, assumed to be potential candidates as catalytic residues. Amacr from Mycobacterium tuberculosis (MCR) was taken as a representative of the racemases. To determine their importance for efficient catalysis, each of these 26 protic residues of MCR was mutated into an alanine, respectively, and the mutated variants were overexpressed in Escherichia coli. It was found that four variants (R91A, H126A, D156A, and E241A) were properly folded but had much decreased catalytic efficiency. Apparently, Arg 91 , His 126 , Asp 156, and Glu 241 are important catalytic residues of MCR. The importance of these residues for catalysis can be rationalized by the 1.8 Å resolution crystal structure of MCR, which shows that the catalytic site is at the interface between the large and small domain of two different subunits of the dimeric enzyme. This crystal structure is the first structure of a complete enzyme of the bile acid synthesis pathway. It shows that MCR has unique structural features, not seen in the structures of the sequence related formyl-CoA transferases, suggesting that the family III CoA transferases can be subdivided in at least two classes, being racemases and CoA transferases.␣-Methylacyl-CoA racemase (Amacr) 1 catalyzes the racemization of (S)-and (R)-enantiomers of a wide spectrum of ␣-methyl-branched carboxyl coenzyme A thioesters (1). In mammals, such substrates are derived from (i) C 27 -bile acid intermediates or (ii) branched-chain fatty acids (pristanic acid), but also 2-arylpropionic acids (ibuprofen), used as non-steroidal anti-inflammatory drugs (Fig. 1), are substrates. It has been shown that Amacr is localized in both peroxisomes and mitochondria (2-4), where racemization of (␣R)-methylacylCoA esters is a condition for their subsequent degradation in ␤-oxidation (5, 6). Consequently, Amacr is required for bile acid synthesis (7) and ␤-oxidation of ␣-methyl-branched fatty acids (8). In mouse, Amacr is an unmodified product of a single gene and it carries both N-and C-terminal targeting sequences for input into mitochondria and peroxisomes, respectively (2). Recently, mutated variants of human Amacr have been shown to be associated with various disease states. Amacr deficiency caused by S52P and L107P sequence changes in human Amacr results in adult-onset sensory motor neuropathy (9), vitamin K deficiency and retinopathy (10), and also in neonatal liver dysfunction (11). Using a knock-out mouse strain, it could be shown that Amacr is essential for detoxification of alimentary phytol, whereas alternative minor pathways...

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P504s

Cited by 326 publications

References 17 publications

Molecular subclassification of kidney tumors and the discovery of new diagnostic markers

Molecular subclassification of kidney tumors and the discovery of new diagnostic markers

Detection and expression of human BK virus sequences in neoplastic prostate tissues

α-Methylacyl-CoA Racemase from Mycobacterium tuberculosis

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