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2.
Br J Dermatol ; 165(1): 106-14, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21428977

ABSTRACT

BACKGROUND: Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD. OBJECTIVES: To investigate further the spectrum of FLG-null mutations in Chinese patients and to compare it with that in other populations. METHODS: We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate-to-severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls. Results In total, 22 FLG-null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD [Fisher's exact test; P = 5·3 × 10⁻9; odds ratio (OR) 3·3], palmar hyperlinearity (Fisher's exact test; P = 9·0 × 10⁻¹5; OR 5·8), keratosis pilaris (Fisher's exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063). CONCLUSIONS: This study emphasizes the wider genetic landscape of FLG-null mutations in Asia that is slowly emerging.


Subject(s)
Asian People/genetics , Dermatitis, Atopic/genetics , Intermediate Filament Proteins/genetics , Mutation , White People/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Cohort Studies , DNA Mutational Analysis , Dermatitis, Atopic/ethnology , Female , Filaggrin Proteins , Gene Frequency , Genetic Predisposition to Disease/genetics , Genotype , Humans , Ichthyosis Vulgaris/genetics , Infant , Male , Middle Aged , Singapore , Young Adult
3.
Allergy ; 66(7): 934-40, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21261659

ABSTRACT

BACKGROUND: Filaggrin, coded by FLG, is the main source of several major components of natural moisturizing factor (NMF) in the stratum corneum (SC), including pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA). Loss-offunction mutations in FLG lead to reduced levels of filaggrin degradation products in the SC. It has recently been suggested that expression of filaggrin may additionally be influenced by the atopic inflammatory response. In this study, we investigated the levels of several breakdown products of filaggrin in the SC in healthy controls (CTRL) and patients with atopic dermatitis (AD) in relation to FLG null allele status. We examined the relationship between NMF (defined here as the sum of PCA and UCA) and AD severity. METHODS: The SC levels of filaggrin degradation products including PCA, UCA, histidine (HIS) and tyrosine were determined in 24 CTRL and 96 patients with moderate-to-severe AD. All subjects were screened for 11 FLG mutations relevant for the study population. RESULTS: The levels of PCA, UCA and HIS correlated with FLG genotype. Furthermore, these levels were higher in the CTRL when compared to AD patients with no FLG mutations. Multiple regression analysis showed that NMF levels were independently associated with FLG genotype and severity of disease. CONCLUSION: Decreased NMF is a global feature of moderate-to-severe AD; within AD, FLG genotype is the major determinant of NMF, with disease severity as a secondary modifier. NMF components are reliably determined by a noninvasive and relatively inexpensive tape stripping technique.


Subject(s)
Dermatitis, Atopic/physiopathology , Intermediate Filament Proteins/genetics , Pyrrolidonecarboxylic Acid/metabolism , Severity of Illness Index , Skin/metabolism , Urocanic Acid/metabolism , Child , Child, Preschool , Dermatitis, Atopic/genetics , Dermatitis, Atopic/metabolism , Female , Filaggrin Proteins , Genetic Predisposition to Disease , Genotype , Humans , Intermediate Filament Proteins/metabolism , Male , Mutation
4.
Oncogene ; 29(49): 6418-27, 2010 Dec 09.
Article in English | MEDLINE | ID: mdl-20729907

ABSTRACT

Mutations in the adenomatous polyposis coli (APC) tumour suppressor are the key initiating event of colorectal cancer. Although the control of WNT signalling is well established as a central tumour-suppressive function, the significance of APC in regulating chromosome instability is less well established. In this study, we test whether APC-deficient cells have a functional spindle assembly checkpoint (SAC) in vivo by examining the response of these cells to Taxol and Vinorelbine. We also show for the first time that APC deficiency compromises the arrest response to Taxol in vivo. This effect is independent of the role that APC has in WNT signalling. At higher levels of Taxol, APC-deficient cells arrest as efficiently as wild-type cells. Importantly, this dose of Taxol strongly suppresses intestinal tumourigenesis in models of benign (APC(Min/+) mouse) and invasive (AhCreER(+)APC(fl/+)PTEN(fl/fl)) cancer. In contrast to intestinal enterocytes with a general SAC defect because of Bub1 (budding uninhibited by benzimidazole 1) deletion, APC-deficient enterocytes arrest equivalently to wild type when treated with Vinorelbine. This suggests that the failed arrest in response to Taxol is because of a specific defect in microtubule stabilization following Taxol treatment rather than a general role of the APC protein in the mitotic spindle checkpoint. In summary, this study clarifies the role of APC as a mitotic spindle checkpoint protein in vivo and shows that APC-deficient cells have a compromised response to Taxol.


Subject(s)
Adenomatous Polyposis Coli Protein/physiology , Adenomatous Polyposis Coli/drug therapy , Antineoplastic Agents, Phytogenic/therapeutic use , Drug Resistance, Neoplasm/genetics , Paclitaxel/therapeutic use , Spindle Apparatus/metabolism , Adenomatous Polyposis Coli/pathology , Adenomatous Polyposis Coli Protein/genetics , Animals , Cell Cycle/drug effects , Cell Cycle/genetics , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Chromosomal Instability/genetics , Enterocytes/drug effects , Enterocytes/pathology , Male , Mice , Mice, Inbred C57BL , Protein Serine-Threonine Kinases/genetics , Sequence Deletion , Spindle Apparatus/genetics , Vinblastine/analogs & derivatives , Vinblastine/therapeutic use , Vinorelbine , Wnt Proteins/metabolism
5.
J Mol Biol ; 308(1): 27-38, 2001 Apr 20.
Article in English | MEDLINE | ID: mdl-11302704

ABSTRACT

Reversible histone acetylation changes the chromatin structure and can modulate gene transcription. Mammalian histone deacetylase 1 (HDAC1) is a nuclear protein that belongs to a growing family of evolutionarily conserved enzymes catalysing the removal of acetyl residues from core histones and other proteins. Previously, we have identified murine HDAC1 as a growth factor-inducible protein in murine T-cells. Here, we characterise the molecular function of mouse HDAC1 in more detail. Co-immunoprecipitation experiments with epitope-tagged HDAC1 protein reveal the association with endogenous HDAC1 enzyme. We show that HDAC1 can homo-oligomerise and that this interaction is dependent on the N-terminal HDAC association domain of the protein. Furthermore, the same HDAC1 domain is also necessary for in vitro binding of HDAC2 and HDAC3, association with RbAp48 and for catalytic activity of the enzyme. A lysine-rich sequence within the carboxy terminus of HDAC1 is crucial for nuclear localisation of the enzyme. We identify a C-terminal nuclear localisation domain, which is sufficient for the transport of HDAC1 and of reporter fusion proteins into the nucleus. Alternatively, HDAC1 can be shuttled into the nucleus by association with another HDAC1 molecule via its N-terminal HDAC association domain. Our results define two domains, which are essential for the oligomerisation and nuclear localisation of mouse HDAC1.


Subject(s)
Histone Deacetylases/chemistry , Histone Deacetylases/metabolism , Transcription Factors , Active Transport, Cell Nucleus , Amino Acid Motifs , Amino Acid Sequence , Animals , Carrier Proteins/metabolism , Cell Line , Cell Nucleus/metabolism , Conserved Sequence/genetics , Epitopes/genetics , Epitopes/metabolism , Hemagglutinins, Viral/genetics , Hemagglutinins, Viral/metabolism , Histone Deacetylase 1 , Histone Deacetylases/genetics , Humans , Lysine/genetics , Lysine/metabolism , Mice , Molecular Sequence Data , Mutation/genetics , Nuclear Localization Signals , Nuclear Proteins/metabolism , Protein Binding , Protein Structure, Quaternary , Protein Structure, Tertiary , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Repressor Proteins/metabolism , Retinoblastoma-Binding Protein 4 , Sequence Alignment , Sin3 Histone Deacetylase and Corepressor Complex
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