: Atherosclerosis is the leading cause of coronary artery disease, peripheral vascular disease and cerebrovascular disease in this country, afflicting millions of Americans. The pathogenesis of atherosclerosis is complex, yet dysregulated proliferation of smooth muscle cells is implicated as an important proponent. A genetic study using p53 knockout mice suggested that he presence of functional 053 is preventive against atherosclerosis in a hyperlipidemic environment. In addition, studies have indicated that the presence of p53 inhibitors, such as Mdm-2 and IE84, accelerates atherosclerosis. Our laboratory identified a new p53 inhibitor and designated it as fortilin. Characterization of fortilin in our laboratory so far showed: (1) The peptide sequence of fortilin is highly conserved among different species. (2) The message of fortilin is resent in all normal human tissues while its expression is greater in cancerous cell lines. (3) Fortiin expression is more prominent in malignant than I benign tissue. (4) Fortilin binds p53. (5) The overexpression prevents of fortilin prevents cells from undergoing etoposide-induced apoptosis. (6) The over expression of fortilin prevents cells from undergoing apoptosis induced by the expression of p53. (7) The overexpression of fortilin inhibits p53-mediated transactivation of BAX, a pro-apoptotic molecule. (8) The expression of fortilin is up regulated in atheroma. There are three major Specific Aims proposed to further characterize fortilin and the fortilin-p53 interaction:
Aim 1 : To define the region of fortilin that interacts with p53 and other molecules. We will first determine which domain of fortilin participates in p53 binding by generating and evaluating various deletion mutants for their ability to interact with fortilin (Aim1.1). We will then identify the region of that fortilin domain that is required for the interaction with p53 (Aim1.2). Finally, we will establish whether fortilin is covalently modified by sentrin and other ubiquitin-like molecules (Aim 1.3).
Aim 2 : To characterize the region of p53 that interacts with fortilin and other molecules. In this major aim, we determine which domain (Aim 2.1) and region (Aim 2.2) of p53 participates in fortilin binding, using deletion and point mutants, respectively. We will then evaluate whether the fortilin-binding region of p53 is required for p53 to interact with Mdm2, Mdm-X and BRCA2, p53 binding and inhibitory molecules (Aim 2.3).
Aim 3 : To investigate the regulatory role of fortilin-p53 interaction in apoptosis. We will determine whether fortilin inhibits p53-mediatd apoptosis (Aim3.1), p53-mediated transactivation of Bax (Aim 3.2) and p53 binding to the Bas-responsive element (Aim 3.3) THROUGH ITS DIRECT binding of p53. Knowledge gained I this proposal will enable us to have a solid foundation for the future intervention of human atherosclerosis.
| Pinkaew, Decha; Chattopadhyay, Abhijnan; King, Matthew D et al. (2017) Fortilin binds IRE1? and prevents ER stress from signaling apoptotic cell death. Nat Commun 8:18 |
| Chattopadhyay, Abhijnan; Pinkaew, Decha; Doan, Hung Q et al. (2016) Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice. Sci Rep 6:18701 |
| Pinkaew, Decha; Le, Rachel J; Chen, Yanjie et al. (2013) Fortilin reduces apoptosis in macrophages and promotes atherosclerosis. Am J Physiol Heart Circ Physiol 305:H1519-29 |
| Pinkaew, Decha; Hutadilok-Towatana, Nongporn; Teng, Ba-Bie et al. (2012) Morelloflavone, a biflavonoid inhibitor of migration-related kinases, ameliorates atherosclerosis in mice. Am J Physiol Heart Circ Physiol 302:H451-8 |
| Chen, Yanjie; Fujita, Takayuki; Zhang, Di et al. (2011) Physical and functional antagonism between tumor suppressor protein p53 and fortilin, an anti-apoptotic protein. J Biol Chem 286:32575-85 |
| Pinkaew, Decha; Cho, Sung Gook; Hui, David Y et al. (2009) Morelloflavone blocks injury-induced neointimal formation by inhibiting vascular smooth muscle cell migration. Biochim Biophys Acta 1790:31-9 |
| Koide, Yuichi; Kiyota, Tomomi; Tonganunt, Moltira et al. (2009) Embryonic lethality of fortilin-null mutant mice by BMP-pathway overactivation. Biochim Biophys Acta 1790:326-38 |
| Fujita, Takayuki; Felix, Kumar; Pinkaew, Decha et al. (2008) Human fortilin is a molecular target of dihydroartemisinin. FEBS Lett 582:1055-60 |
| Mnjoyan, Zakar H; Doan, Dennis; Brandon, Jimi Lynn et al. (2008) The critical role of the intrinsic VSMC proliferation and death programs in injury-induced neointimal hyperplasia. Am J Physiol Heart Circ Physiol 294:H2276-84 |
| Graidist, Potchanapond; Yazawa, Michio; Tonganunt, Moltira et al. (2007) Fortilin binds Ca2+ and blocks Ca2+-dependent apoptosis in vivo. Biochem J 408:181-91 |
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