Meta-analysis found that BRAF mutation is associated with LNM, stage, extrathyroidal extension, tumor size, male gender, multifocality, absence of capsule, classic PTC, and tall-cell variant PTC in PTC. However, almost all studies were retrospective and only two of 32 included patients who had undergone routine central lymph node dissection, emphasizing the need for well-designed studies to appropriately examine this association before making important clinical decisions.
Aberrant expression of the alpha-fetoprotein (AFP) gene is characteristic of a majority of hepatocellular carcinoma cases and serves as a diagnostic tumor-specific marker. By dissecting regulatory mechanisms through electromobility gel shift, transient-transfection, Western blot, and in vitro transcription analyses, we find that AFP gene expression is controlled in part by mutually exclusive binding of two trans-acting factors, p53 and hepatic nuclear factor 3 (HNF-3). HNF-3 protein activates while p53 represses AFP transcription through sequence-specific binding within the previously identified AFP developmental repressor domain. A single mutation within the DNA binding domain of p53 protein or a mutation of the p53 DNA binding element within the AFP developmental repressor eliminates p53-repressive effects in both transient-transfection and cell-free expression systems. Coexpression of p300 histone acetyltransferase, which has been shown to acetylate p53 and increase specific DNA binding, amplifies the p53-mediated repression. Western blot analysis of proteins present in developmentally staged, liver nuclear extracts reveal a one-to-one correlation between activation of p53 protein and repression of AFP during hepatic development. Induction of p53 in response to actinomycin D or hypoxic stress decreases AFP expression. Studies in fibroblast cells lacking HNF-3 further support a model for p53-mediated repression that is both passive through displacement of a tissue-specific activating factor and active in the presence of tissue-specific corepressors. This mechanism for p53-mediated repression of AFP gene expression may be active during hepatic differentiation and lost in the process of tumorigenesis.Loss of tumor suppressor p53 function has broad-ranging effects on many cellular processes, including DNA repair, DNA replication, and cell cycle control, and is a critical step in the progression of many human cancers (reviewed in references 32, 46, and 51). p53 is frequently portrayed as an emergency response molecule, activated only under conditions of high stress or DNA damage. However, studies of cellular differentiation and p53 function (24,55,66,70,80), as well as overexpression of p53 in transgenic mice (24) or knockout of its genetic repressor MDM 2 (10), have underscored the importance of maintaining tightly regulated p53 activity during normal development.The pleiotropic effects of p53 are most often ascribed to p53-mediated transcriptional activation of downstream target genes (reviewed in references 32, 46, and 51). However, studies of apoptosis inhibitors, including adenovirus E1B-19kD, bcl-2, and WT-1 proteins (56, 68), indicate that p53 may also control cell growth and death by means other than transcription activation. One proposed mechanism is p53-mediated repression of gene expression. For example, activation of p53 protein by UV irradiation of murine embryo-derived fibroblast cell lines downregulated transcription of genes involved in the apoptotic response of cells to stress, e.g., the MAP4 micr...
S100A7, also called psoriasin, is a member of the S100 multigene family that is encoded in the epidermal differentiation complex on chromosome 1q21. S100A7 is highly expressed in epidermal hyperproliferative disease; however, its function is not well understood. These studies show high levels of monomer and covalently crosslinked high molecular weight S100A7 in human wound exudate and granulation tissue. Immunohistological studies suggest that this S100A7 is produced by keratinocytes surrounding the wound and is released into the wound exudate. S100A7 is also detected in keratinocyte-conditioned cell culture medium. Studies using recombinant S100A7 indicate that it adheres to and reduces E. coli survival. Mutation of the conserved carboxyl-terminal EF-hand calcium-binding motif or heat denaturation slightly reduces S100A7 antibacterial activity; however, the antibacterial activity is destroyed by protease treatment. Mutation of the zinc-binding motif, located at the C-terminus, reduces antibacterial activity; however, this reduction can be reversed by simultaneous removal of the amino terminus. This indicates the surprising finding that the central region of S100A7, including only amino acids 35-80, is sufficient for full antibacterial activity. These studies also indicate that reduced S100A7 association with bacteria is associated with reduced antibacterial activity.
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