The long range goals of this laboratory are to understand and ultimately control both normal and abnormal cell growth in blood vessel walls. Platelet derived growth factor(s) (PDGF) release locally during hemostasis and thrombosis appear to influence both cell migration into blood vessel walls and to initiate the paracrine and perhaps the autocrine regulation of their growth. The product of the v-sis oncogene, p28v-sis, shares near identify with PDGF in its mitogenic activity and chemotactic potency and thus is well suited as a model to pursue the associated inflammatory and proliferative responses associated with thrombosis and hemostasis, and perhaps with the pathological process of atherosclerosis. It is planned to analyze cells which express PDGF-like proteins and to seek mechanisms and sites of activity whereby these proteins initiate DNA synthesis and cell proliferation, using techniques of cell biology, biochemistry, and molecular biology.
The specific aims are to analyze the processing of both the v-sis gene product and the PDGF cell surface receptor and to determine at which stage of processing the v-sis gene product may interact with the PDGF receptor as each is processed through the endoplasmic reticulum/Golgi complex and to determine whether the PDGF receptor is activated in SSV-transformed cells prior to expression at the cell surface. It is also planned to express cDNA clones of the PDGF A-chain a) to determine if the PDGF A-chain coupled to a strong promoter transforms Nr6 cells, b) to synthesize and purify A-chain homodimers for further study, c) to analyze the processing of the PDGF A-chain, and d) to determine if the A-chain interacts with the PDGF receptor. We also plan to isolate, sequence, and analyze the 5' upstream DNA sequences of the PDGF A-chain gene and to analyze the regulation of the PDGF receptor at the level of gene transcription and translation, and at the level of expression and degradation of the receptor protein at the cell surface. These experiments seek to fill gaps in the existing knowledge of the basic mechanisms whereby growth factors stimulate normal cell proliferation and perhaps play roles in the pathological processes of atherosclerosis and fibrotic diseases, with the long range goal of providing approaches to rational therapeutic means for controlling these processes in appropriate situations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL031102-15
Application #
2445115
Study Section
Special Emphasis Panel (NSS)
Project Start
1989-07-01
Project End
1998-06-30
Budget Start
1997-09-30
Budget End
1998-06-30
Support Year
15
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Herradon, Gonzalo; Ezquerra, Laura; Nguyen, Trang et al. (2005) Midkine regulates pleiotrophin organ-specific gene expression: evidence for transcriptional regulation and functional redundancy within the pleiotrophin/midkine developmental gene family. Biochem Biophys Res Commun 333:714-21
Pariser, Harold; Ezquerra, Laura; Herradon, Gonzalo et al. (2005) Fyn is a downstream target of the pleiotrophin/receptor protein tyrosine phosphatase beta/zeta-signaling pathway: regulation of tyrosine phosphorylation of Fyn by pleiotrophin. Biochem Biophys Res Commun 332:664-9
Liu, J J; Wang, Z Y; Deuel, T F et al. (1999) Imbalanced expression of functionally different WT1 isoforms may contribute to sporadic unilateral Wilms' tumor. Biochem Biophys Res Commun 254:197-9
Zhang, N; Yeh, H J; Zhong, R et al. (1999) A dominant-negative pleiotrophin mutant introduced by homologous recombination leads to germ-cell apoptosis in male mice. Proc Natl Acad Sci U S A 96:6734-8
Silos-Santiago, I; Yeh, H J; Gurrieri, M A et al. (1996) Localization of pleiotrophin and its mRNA in subpopulations of neurons and their corresponding axonal tracts suggests important roles in neural-glial interactions during development and in maturity. J Neurobiol 31:283-96
Kim, H R; Upadhyay, S; Li, G et al. (1995) Platelet-derived growth factor induces apoptosis in growth-arrested murine fibroblasts. Proc Natl Acad Sci U S A 92:9500-4
Wang, Z Y; Qiu, Q Q; Huang, J et al. (1995) Products of alternatively spliced transcripts of the Wilms' tumor suppressor gene, wt1, have altered DNA binding specificity and regulate transcription in different ways. Oncogene 10:415-22
Wang, Z Y; Qiu, Q Q; Gurrieri, M et al. (1995) WT1, the Wilms' tumor suppressor gene product, represses transcription through an interactive nuclear protein. Oncogene 10:1243-7
Kawahara, R S; Deng, Z W; Denkinger, D J et al. (1994) Role of serine/threonine protein kinases in the induction of JE, a platelet-derived growth factor inducible gene. Biochem Biophys Res Commun 203:1815-20
Deng, Z W; Denkinger, D J; Peterson, K E et al. (1994) Glucocorticoids negatively regulate the transcription of KC, the mouse homolog of MGSA/GRO. Biochem Biophys Res Commun 203:1809-14

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