Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylcrotonylglycinuria (MCG; MIM 210200) is an autosomal recessive inherited human disorder caused by the deficiency of 3-methylcrotonyl-CoA carboxylase (MCC, E.C.6.4.1.4), involved in leucine catabolism. This mitochondrial enzyme is one of the four biotin-dependent carboxylases known in humans. MCC is composed of two different types of subunits, alpha and beta, encoded by the nuclear genes MCCA and MCCB, respectively, recently cloned and characterized. Several mutations have been identified, in both genes, the majority are missense mutations along with splicing mutations and small insertions/deletions. We have expressed four missense mutations, two MCCA and two MCCB mapping to highly evolutionarily conserved residues, by transient transfection of SV40-transformed deficient fibroblasts in order to confirm their pathogenic effect. All the missense mutations expressed resulted in null or severely diminished MCC activity providing direct evidence that they are disease-causing ones. The MCCA mutations have been analysed in the context of three-dimensional structural information modelling the changes in the crystallized biotin carboxylase subunit of the Escherichia coli acetyl-CoA carboxylase. The apparent severity of all the MCC mutations contrasts with the variety of the clinical phenotypes suggesting that there are other cellular and metabolic unknown factors that affect the resulting phenotype.
Mol Genet Metab 2003 Nov
PMID:Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria. 1468 Sep 78

A cDNA encoding a potassium channel of the two-pore domain family (K2p) of leak channels was cloned from the CNS of the marine opisthobranch Aplysia californica. This is the first sequence of the K2p family identified in molluscs and has been named AcK2p1. The deduced amino acid sequence is homologous to channels of the mammalian two-pore domain halothane inhibited (THIK) subfamily, bearing 46% identity to THIK-1 (KCNK 13) and 48% to THIK-2 (KCNK12). We used in-situ hybridization to analyze the distribution of this class of channels in the CNS. AcK2p1 is specifically expressed in many central neurons of all major ganglia including the largest identified neurons MCC, R2 and LP1. The highest expression of AcK2p1 was detected in an asymmetrical and distinct cluster of up to 30 cells located at the dorsal-medial region of the right pleural ganglion. The neuron-specific distribution seen in the molluscan CNS is consistent with data from mammals that indicate THIK is only expressed in restricted neuronal populations, suggesting its involvement in both the maintenance of neuronal phenotype and in the specific functional role of these neurons in their respective networks.
Brain Res Mol Brain Res 2004 Aug 23
PMID:Identification and distribution of a two-pore domain potassium channel in the CNS of Aplysia californica. 1530 18

Colorectal carcinomas are characterized by multiple genetic aberrations that occur during tumorigenesis. Several tumor suppressor genes associated with colorectal carcinoma have been identified: MCC, APC, p53, nm23-H1, DCC, DPC4. We examined 73 cases of sporadic human colon cancer and corresponding normal tissue samples to evaluate the loss of heterozygosity (LOH) at the APC gene loci. The purpose of this study was also to evaluate whether the LOH at the APC gene is associated with clinicopathological characteristics in sporadic colon cancer. We also investigated presence and the frequency of the most common APC gene mutations and APC E1317Q and I1307K germ-line variants in Croatian colorectal cancer patients. Five markers in all patients were found to be heterozygous and informative for LOH analysis. LOH at the APC locus was detected in 30.1% of tumors were examined. The majority of APC gene LOH was observed in Dukes' B (55.6%) and in the moderately differentiated tumors (42.9%). Only 1309 APC gene mutation was detected in our samples. In one tumor sample, a new sporadic mutation of the APC gene in codon 1374 was detected. APC E1317Q and I1307K germ-line variants were not detected in our population. But APC E1317Q sporadic mutation was found in one tumor sample.
Exp Mol Pathol 2004 Dec
PMID:APC gene loss of heterozygosity, mutations, E1317Q, and I1307K germ-line variants in sporadic colon cancer in Croatia. 1550 35

Merkel cell carcinoma (MCC) is an uncommon, aggressive neuroendocrine carcinoma of the skin. Its prognosis is poor because of involvement of regional lymph nodes and metastases to distant sites such as bone, liver, lung, and brain. Very few metastases are reported to the gastrointestinal tract. Several studies have shown the utility of cytokeratin 20 to differentiate MCC from other small round blue cell tumors, particularly those with neuroendocrine differentiation. In this case report, we present an unusual metastasis to the stomach and the utility of cytokeratin 20 immunohistochemistry to confirm MCC.
Appl Immunohistochem Mol Morphol 2004 Dec
PMID:Cytokeratin 20 confirms merkel cell metastasis to stomach. 1553 35

Apoptosis and/or differentiation induction caused by the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand is a promising approach to cancer therapy. The thiazolidinedione derivative MCC-555 has an apoptotic activity in human colorectal cancer cells, accompanied by up-regulation of a proapoptotic nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in a PPARgamma-independent manner. Treatment with MCC-555 resulted in the induction of NAG-1 expression and apoptosis in HCT-116 cells. Down-regulation of NAG-1 by small interfering RNA suppressed MCC-555-induced apoptosis. MCC-555 was found to affect NAG-1 mRNA stability. To further define the underlying mechanism of RNA stability affected by MCC-555, we cloned the 3'-untranslated region (3'UTR) of human NAG-1 mRNA, which contains four copies of an AU-rich element (ARE), downstream from the luciferase gene. The reporter activity was reduced to approximately 70% by inserting the 3'UTR. In addition, deletion of ARE sequences in the 3'UTR or MCC-555 treatment substantially restored activity. This effect of MCC-555 on the ARE-mediated mRNA degradation was inhibited by extracellular signal-regulated kinase (ERK) pathway inhibitors. Subsequently, rapid phosphorylation of ERK1/2 by MCC-555 treatment was detected. Moreover, ERK small interfering RNA suppressed MCC-555-induced NAG-1 expression. These results suggest that ARE sequences in the 3'UTR of the NAG-1 gene contribute to mRNA degradation and ERK1/2 phosphorylation is responsible for the stabilization of NAG-1 mRNA. These findings may provide a novel explanation for the antitumorigenic and/or proapoptotic action of MCC-555 in human colorectal cancer and the ability of pharmacologic approaches to be used against diseases caused by alterations of RNA stability.
Mol Cancer Ther 2006 May
PMID:A novel peroxisome proliferator-activated receptor gamma ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells. 1673 69

Primary ovarian small cell carcinomas are rare tumors that are subclassified into the hypercalcemic (HT) and the pulmonary type (PT), and each tumor type has different clinicopathologic characteristics. However, overlapping morphologic features can make the distinction between these lesions difficult. The PT small cell carcinoma is very rare, with only one series and a few case reports published. The authors report two additional cases of this entity and also report for the first time the immunohistochemical finding of perinuclear dot-like staining with cytokeratin 20. This staining pattern has been reported only for Merkel cell carcinoma and salivary gland small cell carcinoma. The authors suggest that the punctate CK20 staining is a useful tool in the diagnostic distinction of PT small cell carcinoma from HT small cell carcinoma, from other primary ovarian tumors such as granulosa cell tumors, and from metastatic neuroendocrine tumors originating at primary sites such as the lung. Since the authors' conclusions are based on two cases of this rare entity, additional cases will need to be studied in the future.
Appl Immunohistochem Mol Morphol 2006 Jun
PMID:Perinuclear dot-like cytokeratin 20 staining in small cell neuroendocrine carcinoma of the ovary (pulmonary-type). 1822 17

Increased infiltration of the kidney by mast cells is associated with proteinuria, and interstitial fibrosis in various renal diseases. Mast cells produce serine proteases including tryptase and chymase (MCC) that act via protease-activated receptors (PARs) to induce synthesis of fibrogenic cytokines by renal cells. In the present study, we investigated direct effect of MCC and role of PARs on glomerular albumin permeability (P(alb)). Isolated rat glomeruli were incubated with MCC (0.1, 1, 10, and 100 ng/ml) for 5-30 min in presence or absence of PAR-1 and PAR-2 blocking antibodies. P(alb) was determined from the change in glomerular volume in response to an albumin oncotic gradient. The effect of direct activation of PARs on P(alb) was verified by incubating glomeruli with synthetic hexapeptide known to activate PAR-1 and PAR-2. MCC increased P(alb) of isolated rat glomeruli in a dose- and time-dependent manner. Blocking PAR-2 prevented MCC-mediated increase in P(alb). RT-PCR analysis of glomerular RNA demonstrated the presence of constitutively expressed PAR-1, -2, and -3 and low levels of PAR-4. In addition, direct activation of PAR-2 by hexapeptide SLIGKV increased P(alb) comparable to MCC, whereas PAR-1 activation by TFLLRN had no effect on P(alb). Our results document that MCC induces increase in P(alb) and that this effect is mediated through PAR-2. MCC may also play a role in renal scarring. We propose that inhibiting MCC activity or blocking the activation of PAR-2 may provide new targets for therapy in renal diseases.
Mol Cell Biochem 2007 Mar
PMID:Chymase increases glomerular albumin permeability via protease-activated receptor-2. 1710 4

3-MCC deficiency is among the most common inborn errors of metabolism identified on expanded newborn screening (1:36,000 births). However, evidence-based guidelines for diagnosis and management of this disorder are lacking. Using the traditional Delphi method, a panel of 15 experts in inborn errors of metabolism was convened to develop consensus-based clinical practice guidelines for the diagnosis and management of 3-MCC screen-positive infants and their mothers. The Oxford Centre for Evidence-based Medicine system was used to grade the literature review and create recommendations graded from A (evidence level of randomized clinical trials) to D (expert opinion). Panelists reviewed the initial evaluation of the screen-positive infant-mother dyad, diagnostic guidelines, and management of diagnosed patients. Grade D consensus recommendations were made in each of these three areas. The panel did not reach consensus on all issues. This consensus protocol is intended to assist clinicians in the diagnosis and management of screen-positive newborns for 3-MCC deficiency and to encourage the development of evidence-based guidelines.
Mol Genet Metab 2008 Apr
PMID:A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency. 1815 30

Cyclooxygenase-2 (COX-2) is involved in the development and progression of many tumors, and its inhibition has been shown to block tumor growth. This study examined COX-2 expression in primary and metastatic Merkel cell carcinoma (MCC). Formalin-fixed paraffin-embedded tissues from 26 primary MCCs and 7 lymph node metastases were stained immunohistochemically with a monoclonal antibody directed against COX-2, and the percentage and intensity of staining were analyzed semiquantitatively. Immunopositivity for COX-2 was found in 20 primary tumors (77%), and was diffuse in 16 of them (80%). Staining intensity was strong in 5 tumors (19%), moderate in 6 (23%), and weak in 9 (35%). Five metastases (71%) showed similar staining. Prominent mitotic activity was associated with more diffuse COX-2 immunopositivity. No association was found between COX-2 expression and outcome. This study confirms that most MCCs express COX-2 and shows that COX-2 expression is related to one parameter of aggressive behavior--a high mitotic rate--but not to any others. The possibility of treating MCC with COX-2 inhibitors should be considered.
Appl Immunohistochem Mol Morphol 2008 Oct
PMID:Cyclooxygenase-2 expression in primary and metastatic Merkel cell carcinoma. 1859 70

A large body of studies has suggested that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, such as thiazolidinedione, are potent candidates for chemopreventive agents. MCC-555 is a PPARgamma/alpha dual agonist and has been shown previously to induce apoptosis in vitro; however, the molecular mechanisms by which MCC-555 affects antitumorigenesis in vivo are poorly understood. In this study, we explored the antitumorigenic effects of MCC-555 both in cell culture and in Apc-deficient mice, an animal model for human familial adenomatous polyposis. MCC-555 increased MUC2 expression in colorectal and lung cancer cells, and treatment with the PPARgamma antagonist GW9662 revealed that MUC2 induction by MCC-555 was mediated in a PPARgamma-dependent manner. Moreover, MCC-555 increased transcriptional activity of human and mouse MUC2 promoters. Subsequently, treatment with MCC-555 (30 mg/kg/d) for 4 weeks reduced the number of small intestinal polyps to 54.8% of that in control mice. In agreement with in vitro studies, enhanced Muc2 expression was observed in the small intestinal tumors of Min mice treated with MCC-555, suggesting that MUC2 expression may be associated at least in part with the antitumorigenic action of MCC-555. In addition, highly phosphorylated extracellular signal-regulated kinase (ERK) was found in the intestinal tumors of MCC-555-treated Min mice, and inhibition of the ERK pathway by a specific inhibitor markedly suppressed MCC-555-induced Muc2 expression in vitro. Overall, these results indicate that MCC-555 has a potent tumor suppressor activity in intestinal tumorigenesis, likely involving MUC2 up-regulation by ERK and PPARgamma pathways.
Mol Cancer Ther 2008 Sep
PMID:Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in ApcMin/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways. 1879 Jul 58


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