Phosphorylation status of Fas-associated death domain-containing protein (FADD) is associated with prostate cancer progression
ABSTRACT It has recently been demonstrated that phosphorylation of FADD at serine 194 plays an important role in the induction of apoptosis by anti-cancer drugs in human prostate cancer cells. The present study has assessed whether this phosphorylation status is valuable as a marker for human prostate cancer progression, and has investigated its biological role in cell growth. Immunohistochemical studies revealed much higher phosphorylation of FADD at serine 194 in normal epithelial cells than in cancer cells, although FADD was found to be highly expressed to the same extent in both cases. The positivity for phosphorylated FADD was significantly lower for patients with a Gleason score greater than or equal to 7, a positive surgical margin, extracapsular or seminal vesicle invasion. In addition, a relationship was also apparent in cancer cells refractory to neoadjuvant hormonal therapy. Interestingly, in Gleason score 3 + 4 tumours, the positivity for FADD phosphorylation was statistically increased by neoadjuvant hormonal therapy, resulting in a reduced percentage of cases with a positive surgical margin and extracapsular invasion. In vitro data showed different functions of phosphorylated and non-phosphorylated FADD: in normal epithelial cells, overexpression of a phosphorylation-mimicking mutant FADD (S194E) caused G2/M cell-cycle arrest, while a non-phosphorylation-mimicking mutant (S194A) had no effect, whereas S194A overexpression resulted in cell cycle progression and enhanced colony-forming activity in cancer cells, but S194E FADD was without influence. These results clearly demonstrate that transition from phosphorylated FADD to the non-phosphorylated form might be associated with carcinogenesis and that induction of FADD phosphorylation could therefore be a target for chemohormonal therapy of human prostate cancer. Moreover, assessment of FADD phosphorylation may be useful as a new biomarker to predict cancer progression.
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ABSTRACT: FAS-associated protein with death domain (FADD) is a major adaptor protein involved in extrinsic apoptosis, embryogenesis, and lymphocyte homeostasis. Although abnormalities of the FADD/death receptor apoptotic pathways have been established in tumorigenesis, fewer studies have analyzed the expression and role of phosphorylated FADD (pFADD). Our identification of FADD as a lymphoma-associated autoantigen in T-cell lymphoma patients raises the possibility that pFADD, with its correlation with cell cycle, may possess role(s) in human T-cell lymphoma development. This immunohistochemical study investigated pFADD protein expression in a range of normal tissues and lymphomas, particularly T-cell lymphomas that require improved therapies. Whereas pFADD was expressed only in scattered normal T cells, it was detected at high levels in T-cell lymphomas (eg, 84% anaplastic large cell lymphoma and 65% peripheral T cell lymphomas, not otherwise specified). The increased expression of pFADD supports further study of its clinical relevance and role in lymphomagenesis, highlighting phosphorylation of FADD as a potential therapeutic target.Biomarker insights 01/2014; 9:77-84. DOI:10.4137/BMI.S16553
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ABSTRACT: A method to create holistic data models of complex, partly multiscale, workpieces is presented and verified on cutting tools. Different optical sensor principles are applied and the registration strategy is developed to transform partial views taken with single sensors into one coordinate system. Focus of the work is the implementation of automatic registration procedures, based on correlation and segmentation. These novel approaches in coordinate measuring technology are tested and compared. The method is completed by fusing all datasets to one holistic data model, considering the geometry of the workpieces by applying a curvature based segmentation.CIRP Annals - Manufacturing Technology 01/2011; 60(1):539-542. DOI:10.1016/j.cirp.2011.03.055 · 2.54 Impact Factor
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ABSTRACT: The decisions between self-renewal and differentiation of adult stem cells are critical for tissue repair and homeostasis. Here, we show that the apoptotic adaptor Fas-associated Death Domain (FADD) regulated the fate decisions of muscle satellite cells (SCs). FADD phosphorylation was specifically induced in cycling SCs, which was high in metaphase and declined in later anaphase. Furthermore, phosphorylated FADD at Ser191 accumulated in the uncommitted cycling SCs and was asymmetrically localized in the self-renewing daughter SCs. SCs containing a phosphoryl-mimicking mutation at Ser191 of FADD (FADD-D) expressed higher levels of stem-like markers and reduced commitment-associated markers. Moreover, FADD-D suppressed SCs activation and differentiation, which promoted the cycling SCs into a reversible quiescent state. Therefore, these data indicate FADD regulates the fate determination of cycling SCs.Journal of Biological Chemistry 12/2013; 289(8). DOI:10.1074/jbc.M113.533448 · 4.60 Impact Factor