| 1. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 2. |
- Cepeda, D., et al.
(författare)
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CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
- 2013
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 5:7, s. 999-1018
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Tidskriftsartikel (refereegranskat)abstract
- SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors.
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| 5. |
- Movérare-Skrtic, Sofia, et al.
(författare)
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Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
- 2014
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:11, s. 1279-88
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Tidskriftsartikel (refereegranskat)abstract
- The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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| 6. |
- Conaway, H Herschel, et al.
(författare)
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Retinoids and bone
- 2011
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Ingår i: Contemporary aspects of endocrinology. - : InTech. - 9789533073576 ; , s. 443-454
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Conaway, H Herschel, et al.
(författare)
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Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor.
- 2011
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Ingår i: The Journal of biological chemistry. - 1083-351X .- 0021-9258. ; 286:36, s. 31425-36
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Tidskriftsartikel (refereegranskat)abstract
- Increased vitamin A (retinol) intake has been suggested to increase bone fragility. In the present study, we investigated effects of retinoids on bone resorption in cultured neonatal mouse calvarial bones and their interaction with glucocorticoids (GC). All-trans-retinoic acid (ATRA), retinol, retinalaldehyde, and 9-cis-retinoic acid stimulated release of (45)Ca from calvarial bones. The resorptive effect of ATRA was characterized by mRNA expression of genes associated with osteoclast differentiation, enhanced osteoclast number, and bone matrix degradation. In addition, the RANKL/OPG ratio was increased by ATRA, release of (45)Ca stimulated by ATRA was blocked by exogenous OPG, and mRNA expression of genes associated with bone formation was decreased by ATRA. All retinoid acid receptors (RARα/β/γ) were expressed in calvarial bones. Agonists with affinity to all receptor subtypes or specifically to RARα enhanced the release of (45)Ca and mRNA expression of Rankl, whereas agonists with affinity to RARβ/γ or RARγ had no effects. Stimulation of Rankl mRNA by ATRA was competitively inhibited by the RARα antagonist GR110. Exposure of calvarial bones to GC inhibited the stimulatory effects of ATRA on (45)Ca release and Rankl mRNA and protein expression. This inhibitory effect was reversed by the glucocorticoid receptor (GR) antagonist RU 486. Increased Rankl mRNA stimulated by ATRA was also blocked by GC in calvarial bones from mice with a GR mutation that blocks dimerization (GR(dim) mice). The data suggest that ATRA enhances periosteal bone resorption by increasing the RANKL/OPG ratio via RARα receptors, a response that can be inhibited by monomeric GR.
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| 8. |
- Conaway, H Herschel, et al.
(författare)
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Vitamin a metabolism, action, and role in skeletal homeostasis.
- 2013
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Ingår i: Endocrine reviews. - : The Endocrine Society. - 1945-7189 .- 0163-769X. ; 34:6, s. 766-97
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin A (retinol) is ingested as either retinyl esters or carotenoids and metabolized to active compounds such as 11-cis-retinal, which is important for vision, and all-trans-retinoic acid, which is the primary mediator of biological actions of vitamin A. All-trans-retinoic acid binds to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors. RAR-retinoid X receptor heterodimers function as transcription factors, binding RAR-responsive elements in promoters of different genes. Numerous cellular functions, including bone cell functions, are mediated by vitamin A; however, it has long been recognized that increased levels of vitamin A can have deleterious effects on bone, resulting in increased skeletal fragility. Bone mass is dependent on the balance between bone resorption and bone formation. A decrease in bone mass may be caused by either an excess of resorption or decreased bone formation. Early studies indicated that the primary skeletal effect of vitamin A was to increase bone resorption, but later studies have shown that vitamin A can not only stimulate the formation of bone-resorbing osteoclasts but also inhibit their formation. Effects of vitamin A on bone formation have not been studied in as great a detail and are not as well characterized as effects on bone resorption. Several epidemiological studies have shown an association between vitamin A, decreased bone mass, and osteoporotic fractures, but the data are not conclusive because other studies have found no associations, and some studies have suggested that vitamin A primarily promotes skeletal health. In this presentation, we have summarized how vitamin A is absorbed and metabolized and how it functions intracellularly. Vitamin A deficiency and excess are introduced, and detailed descriptions of clinical and preclinical studies of the effects of vitamin A on the skeleton are presented.
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| 9. |
- Figueroa, Jonine D., et al.
(författare)
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Genome-wide association study identifies multiple loci associated with bladder cancer risk
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:5, s. 1387-1398
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Tidskriftsartikel (refereegranskat)abstract
- andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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| 10. |
- Palmqvist, Py, et al.
(författare)
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Interleukin-4 and interleukin-13 inhibit the expression of leukemia inhibitory factor and interleukin-11 in fibroblasts.
- 2012
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Ingår i: Molecular immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 49:4, s. 601-10
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Tidskriftsartikel (refereegranskat)abstract
- Cytokines produced by inflammatory or resident mesenchymal cells play important modulatory roles in the pathogenesis of inflammation induced bone loss. In the present study, the effects of IL-4 and IL-13 on the expression of three osteotropic cytokines in the IL-6 family expressed in human gingival fibroblasts were studied. IL-4Rα and IL-13Rα1 mRNA were constitutively expressed in human gingival fibroblasts. The inflammatory cytokines IL-1β and TNF-α increased expression of IL-6, LIF, and IL-11 mRNA and protein in the gingival fibroblasts. Addition of IL-4 or IL-13 had no effect on IL-6 expression, but significantly inhibited LIF and IL-11 mRNA and protein stimulated by IL-1β and TNF-α. No involvement of NF-κB or STAT1 was observed in the inhibition. STAT6 was phosphorylated at Y641 by treatment with IL-4 and knockdown of STAT6 with siRNA decreased the inhibition of IL-11 and LIF expression by IL-4 in IL-1β and TNF-α stimulated cells. This study suggests that activation of STAT6 by IL-4 and IL-13, through type 2 IL-4 receptors, inhibits production of IL-11 and LIF stimulated by IL-1β and TNF-α in human gingival fibroblasts. A negative modulatory role of IL-4 and IL-13 in osteotropic cytokine production could be a mechanism playing an important inhibitory role in inflammation induced periodontitis.
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