Apolipoprotein(a), (apo(a)), is the distinguishing protein portion of the lipoprotein(a) particle, elevated plasma levels of which are a major risk factor for cardiovascular disease. A search for enhancer elements that control the transcription of the apo(a) gene led to the identification of an upstream element that contains target binding sites for members of the Ets and Sp1 nuclear protein families. The enhancer element functions in either orientation to confer a greater than 10-fold increase in the activity of the apo(a) minimal promoter in cultured hepatocyte cells. Unexpectedly, the enhancer element is located within a LINE retrotransposon element, suggesting that LINE elements may function as mobile regulatory elements to control the expression of nearby genes.
The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10 -17 with a neoR gene. ASPP2 ؊/؊ mice were not viable because of an early embryonic lethal event. Although ASPP2 ؉/؊ mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, ␥-irradiated 6-week-old ASPP2 ؉/؊ mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2 ؉/؉ mice. Primary thymocytes derived from ASPP2 ؉/؊ mice exhibited an attenuated apoptotic response to ␥-irradiation compared with ASPP2 ؉/؉ thymocytes. Additionally, ASPP2 ؉/؊ primary mouse embryonic fibroblasts demonstrated a defective G0/G1 cell cycle checkpoint after ␥-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy.A poptosis-stimulating protein of p53-2 (ASPP2), also known as 53BP2L, encoded by TP53BP2 (1-3), enhances damage-induced apoptosis at least in part through a p53-mediated pathway (2, 4 -6). Depending on cell context and type of stress, ASPP2 levels increase via transcriptional or posttranslational mechanisms after cellular damage (4, 6). In addition to interacting with p53 (and family members) (5, 7), ASPP2 protein, and the 123-aa, amino-terminal, truncated splice isoform 53BP2/Bbp, also known as 53BP2S (3), interacts with several proteins involved in modulating apoptosis and cell growth, including Bcl-2, p65/RelA subunit of NF-B, Yesassociated protein-1, HCV core protein, APCL, and protein phosphatase-1 (8 -13). Additionally, ASPP2 is a direct E2F target gene, suggesting that it is a common link between the Rb/E2F and p53/p73 pathways (14 -16). ASPP2 expression is suppressed in many human cancers, and it has been associated with poor clinical outcome in patients with aggressive nonHodgkin's lymphoma treated with chemotherapy (2, 17-24). These findings suggest that ASPP2 is involved in important tumor suppression networks and the cellular damage response. Overexpression of ASPP2 or Bbp/53BP2S can suppress E1A and ras-mediated transformation of rat embryo fibroblasts (25,26), whereas attenuation of ASPP2 expression promotes clonogenic survival and inhibits apoptosis in cell culture (2, 4, 6) and promotes tumor formation in vivo (27). However, the mechanisms by which reduced ASPP2 expression enhances tumor formation in vivo remain to be elucidated.In this report, we targeted the ASPP2 allele in a mouse by using homologous recombination to explore the in vivo consequences of attenuated ASPP2 expression. We demonstrate that reduced ASPP2 express...
To test directly whether fibrin(ogen) is a key binding site for apolipoprotein(a) [apo(a)] in vessel walls, apo(a) transgenic mice and fibrinogen knockout mice were crossed to generate fibrin(ogen)-deficient apo(a) transgenic mice and control mice. In the vessel wall of apo(a) transgenic mice, fibrin(ogen) deposition was found to be essentially colocalized with focal apo(a) deposition and fatty-streak type atherosclerotic lesions. Fibrinogen deficiency in apo(a) transgenic mice decreased the average accumulation of apo(a) in vessel walls by 78% and the average lesion (fatty streak type) development by 81%. Fibrinogen deficiency in wild-type mice did not significantly reduce lesion development. Our results suggest that fibrin(ogen) provides one of the major sites to which apo(a) binds to the vessel wall and participates in the generation of atherosclerosis.An elevated plasma level of lipoprotein(a) [Lp(a)] is one of the major risk factors for atherosclerosis and its manifestations, myocardial infarction, stroke, and restenosis (see refs. 1 and 2 and references therein). Lp(a) particles contain the lipid and protein components of low-density lipoprotein plus apolipoprotein(a) [apo(a)]. It has been postulated that Lp(a) induces atherosclerosis through its plasminogen-like component apo(a). The human apo(a) gene has been successfully introduced into the mouse, an animal species that normally lacks this gene, and these apo(a) mice develop fatty-streak type lesions in aorta when maintained on a high-fat diet for several months (3). Further experiments in this mouse model have shown a coincidence of apo(a) deposition, decreased level of plasmin, decreased level of active transforming growth factor , and increased level of smooth muscle cell activation and fatty streak type of lesion development in the vessel walls (4). Because of the extensive sequence homology between apo(a) and plasminogen, a potential mechanism by which apo(a) promotes atherosclerosis is to inhibit plasminogen activation to plasmin through competitively inhibiting binding of plasminogen to sites such as fibrin. This hypothesis has been supported by a number of in vitro studies (5-9). The development of fibrinogen-deficient mice (Fib Ϫ/Ϫ mice) allows direct testing of the interaction of fibrin and apo(a) in vivo (10). To test directly whether fibrin(ogen) is a key binding site for apo(a), apo(a) vascular accumulation and lipid lesion were measured in Fib Ϫ/Ϫ ͞apo(a) mice and control mice. MATERIALS AND METHODSMice. The human apo(a) mice created in the C57BL͞6SJL background (3, 11) were backcrossed to C57BL͞6 mice for six
The lipoprotein Lp(a), a major inherited risk factor for atherosclerosis, consists of a low density lipoproteinlike particle containing apolipoprotein B-100 plus the distinguishing component apolipoprotein(a) (apo(a)). Human apo(a) contains highly repeated domains related to plasminogen kringle four plus single kringle five and protease-like domains. Apo(a) is virtually confined to primates, and the gene may have arisen during primate evolution. One exception is the occurrence of an Lp(a)-like particle in the hedgehog. Cloning of the hedgehog apo(a)-like gene shows that it is distinctive in form and evolutionary history from human apo(a), but that it has acquired several common features. It appears that the primate and hedgehog apo(a) genes evolved independently by duplication and modification of different domains of the plasminogen gene, providing a novel type of "convergent" molecular evolution.The lipoprotein Lp(a) 1 has gained increasing attention due to its role as a novel major risk factor for atherosclerosis and for the unusual nature of its distinguishing protein component, apolipoprotein(a) (apo(a)) (see Ref. 1 and references therein). DNA cloning and sequencing revealed the unexpected homology of apo(a) to plasminogen and the presence of 37 domains that are most closely related to the fourth kringle of plasminogen (2). It has since been found that individual alleles contain from ϳ12 to 40 similar or identical kringles, encoding proteins that range in apparent molecular mass fromϳ 250,000 to 800,000 (3). The apo(a) gene likely arose from a duplicated version of the plasminogen gene followed by exon deletions, multiplications, and single base substitutions (2).Although its precise function remains unclear, Lp(a) is concentrated in the artery wall by virtue of binding to fibrin, plasminogen receptors, matrix, and other targets (4 -7). As an inactive homolog of plasminogen, apo(a) competes for the binding and activation of plasminogen and interferes with clot lysis (for reviews, see Refs. 8 -11). It has been speculated that a selective advantage of apo(a) may be its ability to deliver cholesterol to wound sites for cell biosynthesis (12). These properties becomes pathogenic in the face of elevated plasma concentration, exposure to high fat diet, and increased life span. For example, the inhibition of plasminogen activation and the prolonged presence of thrombus on the vessel wall may promote the growth and migration of smooth muscle cells and the development of atherosclerotic lesions through several intermediate pathways (13-15).Of evolutionary as well as practical interest is the observation that the existence of the Lp(a) particle and the apo(a) protein are restricted to Old World monkeys, apes, and humans (16 -20), with one intriguing exception: the insectivore, hedgehog (21). Although some members (e.g. tree shrews and elephant shrews) of the original order Insectivora have now been reclassified, hedgehogs are still considered to be "primitive" extant mammals whose ancestors diverged from other orde...
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