Although still controversial, the presence of mutant p53 in cancer cells may result in more aggressive tumors and correspondingly worse outcomes. The means by which mutant p53 exerts such pro-oncogenic activity are currently under extensive investigation and different models have been proposed. We focus here on a proposed mechanism by which a subset of tumor-derived p53 mutants physically interact with p53 family members, p63 and p73, and negatively regulate their proapoptotic function. Both cell-based assays and knock-in mice expressing mutant forms of p53 support this model. As more than half of human tumors harbor mutant forms of p53 protein, approaches aimed at disrupting the pathological interactions among p53 family members might be of clinical value.
Understanding the interaction of the atherogenic lipoprotein, lipoprotein(a) [Lp(a)], with macrophages may provide important insight into the physiology and pathophysiology of this lipoprotein. We have recently shown that cholesterol loading of macrophages, such as occurs in atheroma foam cells, leads to marked upregulation of a novel receptor activity for native Lp(a) and its plasminogen-like protein component, apoprotein(a) [apo(a)]. We show here that the Lp(a)/apo(a) receptor activity on cholesterol-loaded macrophages is trypsin sensitive, indicating that a cell-surface protein is involved and that the upregulation by cholesterol loading requires new protein synthesis. Ligand studies revealed that the foam cell receptor activity recognizes Lp(a) containing both small and large isoforms of apo(a) as well as rhesus monkey Lp(a), which contains an inactive kringle-4 37 (K4 37 ) lysine-binding domain. Elastase degradation products of plasminogen did not compete for 12 Elevated plasma levels of Lp(a) occur in «=20% of the adult Caucasian population, and there appears to be an association between elevated Lp(a) levels and the occurrence of coronary atherosclerosis.1 -2 Furthermore, cholesterolfed apo(a) transgenic mice develop significantly more atherosclerosis than nontransgenic controls.3 Despite several important hypotheses and in vitro observations regarding possible roles of Lp(a) in atherosclerosis, 47 neither the mechanism of Lp(a) atherogenicity nor the normal physiological roles of the lipoprotein are definitively known. Nonetheless, the interaction of Lp(a) with macrophages is thought to be important, since cholesteryl ester-filled macrophages (foam cells) are a prominent feature of atherosclerotic lesions. 810 In fact, apo(a) has been found to colocalize with foam cells in these lesions. © 1994 American Heart Association, Inc.interaction. Consistent with these data, the degradation of 125 I-r-apo(a) was completely blocked by an anti-Lp(a) polyclonal antibody that does not cross-react with plasminogen. Furthermore, the multiple sialic residues of apo(a) are also not involved in receptor interaction, since desialylated r-apo(a) interacted with foam cells as well as native r-apo(a Previous studies have shown that cultured macrophages internalize and degrade native Lp(a) and apo(a) poorly. 1215 Recent work from our laboratory, however, revealed an Lp(a) receptor activity, different from known lipoprotein receptors, that can be induced in macrophages by cholesterol loading. 16 The interaction of Lp(a) with cholesterol-loaded macrophages is solely dependent on the apo(a) moiety of Lp(a), since lipid-free recombinant apo(a) [r-apo(a)] but not apo(a)-free Lp(a-) is recognized by the foam cell receptor activity. 16In the present study, we investigated whether a cell-surface protein is involved in the foam cell Lp(a)/ apo(a) receptor activity and whether upregulation induced by cholesterol loading requires new protein synthesis. Furthermore, we explored several key properties of ligands that are need...
This report explores the hypothesis that massive cholesteryl ester (CE) accumulation in macrophages, such as that occurring in atheroma foam cells, results in changes in the expression or modification of specific cellular proteins. Two-dimensional (2-D) gel electrophoretic patterns of metabolically labeled cellular proteins from mouse peritoneal macrophages that were loaded with CE (through incubation with acetylated low density lipoprotein [acetyl-LDL] for 4 days) were compared with those of control macrophages. Densitometric analysis of 2-D gel autoradiograms from the cell lysates revealed statistically significant changes in seven cellular proteins (five decreases and two increases). The changes in protein expression (foam cell versus control) ranged from a 458±164% (p<0.001) increase to a 35±34% (p<0.001) decrease (n=U). Incubation of macrophages with /3-very low density lipoprotein, which also increased the CE content of macrophages (albeit to a lesser extent than acetyl-LDL), resulted in changes in five of the seven proteins. In contrast, incubation of cells with LDL, fucoidan, or latex beads, none of which caused CE accumulation, did not lead to significant changes in four of these five proteins. One of these four proteins, which increased fourfold to fivefold in foam cells (Af r =49,00O; isoelectric point of 6.8), was purified by preparative 2-D gel electrophoresis. Internal amino acid sequence of cyanogen bromide fragments of this protein as well as Western blot analysis identified this protein as an isoform of er-enolase. The increased expression of this or-enolase isoform, which was seen as early as day 2 of acetyl-LDL incubation of the macrophages, was diminished by including an inhibitor of cholesterol esterification during the acetyl-LDL incubation period. In conclusion, macrophage foam cell formation is associated with distinct changes in protein expression, including a marked increase in an isoform of a-enolase, suggesting a specific biological adaptation to CE loading. (Arteriosclerosis and Thrombosis 1993;13:264-275
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