1.
Hailey-Hailey disease: investigation of a possible compensatory SERCA2 up-regulation and analysis of SPCA1, p63, and IRF6 expression.
Zhang, D, Li, X, Wang, Z, Zhang, Y, Guo, K, Wang, S, Tu, C, Huo, J, Xiao, S
Archives of dermatological research. 2015;(2):143-9
Abstract
Hailey-Hailey disease (HHD) is caused by heterozygous mutations in the ATP2C1 gene, encoding the secretory pathway Ca(2+) ATPase1 (SPCA1). SPCA1 and sarco/endoplasmic reticulum Ca(2+) ATPase2 (SERCA2) encoded by ATP2A2 are two essential calcium pumps needed for Ca(2+) homeostasis maintenance in keratinocytes. ATP2A2 mutations cause another hereditary skin disorder, Darier's disease (DD). Previously, the compensatory expression of SPCA1 for SERCA2 insufficiency in DD was demonstrated, but it is not known whether a similar compensatory mechanism exists in HHD. Additionally, little is known about the role of p63 and interferon regulatory factor 6 (IRF6), two important regulatory factors involved in keratinocyte proliferation and differentiation, in HHD. Here, we used the skin biopsy samples from patients with HHD and human primary keratinocytes transfected with ATP2C1 siRNA to search for potential pathogenic mechanisms in HHD. We observed normal SERCA2 levels, but reduced p63, and increased IRF6 levels in HHD epidermal tissues and SPCA1-deficient keratinocytes. This suggests that there is no compensatory mechanism by SERCA2 for the SPCA1 deficiency in HHD. Moreover, the abnormal expression of p63 and IRF6 appears to be related to SPCA1 haploinsufficiency, with down-regulation of p63 probably resulting from IRF6 overexpression in HHD. We speculate that a novel pathogenic mechanism involving SPCA1, p63, and IRF6 may play a role in the skin lesions occurring in HHD.
2.
Rare coding variants and X-linked loci associated with age at menarche.
Lunetta, KL, Day, FR, Sulem, P, Ruth, KS, Tung, JY, Hinds, DA, Esko, T, Elks, CE, Altmaier, E, He, C, et al
Nature communications. 2015;:7756
Abstract
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
3.
A novel tri-allelic mutation of TMPRSS6 in iron-refractory iron deficiency anaemia with response to glucocorticoid.
Nie, N, Shi, J, Shao, Y, Li, X, Ge, M, Huang, J, Zhang, J, Huang, Z, Li, D, Zheng, Y
British journal of haematology. 2014;(2):300-3
4.
The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex.
Li, X, Fan, Z
Cancer research. 2010;(14):5942-52
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Abstract
Autophagy is a regulated catabolic process triggered in cells deprived of nutrients or growth factors that govern nutrient uptake. Here, we report that autophagy is induced by cetuximab, a therapeutic antibody that blocks epidermal growth factor receptor function. Cancer cell treatment with cetuximab triggered autophagosome formation, conversion of microtubule-associated protein 1 light chain 3 from its cytoplasmic to membrane-associated form, and increased acidic vesicular organelle formation. Autophagy occurred when cetuximab inhibited the class I phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, but not when it inhibited only the mitogen-activated protein/extracellular signal-regulated kinase kinase/Erk pathway, and it was accompanied by decreased levels of hypoxia inducible factor-1 alpha (HIF-1alpha) and Bcl-2. Stable overexpression of a HIF-1alpha mutant prevented cetuximab-induced autophagy and decrease in Bcl-2 levels. Knockdown of autophagy regulator beclin 1 or cell treatment with autophagy inhibitor 3-methyladenine, a class III PI3K (hVps34) inhibitor, also inhibited cetuximab-induced autophagy. Furthermore, knockdown of beclin 1 or Atg7 or treatment with the lysosome inhibitor chloroquine sensitized cancer cells to cetuximab-induced apoptosis. Mechanistic analysis argued that cetuximab acted by promoting an association between beclin 1 and hVps34, which was inhibited by overexpression of Bcl-2. Our findings suggest that the autophagy protects cancer cells from the proapoptotic effects of cetuximab.