This project is focused on two key findings: (1) Fish oil and omega-3 fatty acids prolong the duration of DNA replication in several proliferating cell lines and this effect is associated with a change in the location of a DNA replication origin; and (2) Levels of PDGF receptor mRNA are significantly increased in fibroblasts treated with fish oil. Dr. Istfan hypothesis is that fatty acids influence the spatial and temporal organization of replication origins by altering the structure of the nuclear membrane. The latter is thought to impact on the organization of the nuclear matrix which has been related to DNA replication origins through specific attachments (scaffold attachment regions, SARs). Alternatively, the degree of nuclear membrane fluidity, a function of fatty acid composition, affects the nuclear pore complex, thus altering the kinetics of nucleocytoplasmic trafficking. Dr. Istfan will test the extent of fatty acid incorporation into nuclear membranes in cell cultures and the cell-free Xenopus replicating system. Membrane fluidity and cell proliferation kinetics will be related to nuclear membrane fatty acids, nuclear membrane pore function, and nuclear matrix organization through studies of SARs and temperature-sensitive nuclear matrix proteins by confocal microscopy. Dr. Istfan also postulates that PDGF receptor regulation compensates for a reduced proliferation signal in fish oil-treated fibroblasts. Studies that examine the relationship between S phase lengthening in fish oil treated fibroblasts and regulation of the PDGF receptor will be initiated. The functional role(s) of this receptor and those of G1/S cyclins in mediating compensatory changes in G1 phase regulation will be examined.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
Program Officer
Kim, Young Shin
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Boston Medical Center
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Istfan, N W; Person, K S; Holick, M F et al. (2007) 1alpha,25-Dihydroxyvitamin D and fish oil synergistically inhibit G1/S-phase transition in prostate cancer cells. J Steroid Biochem Mol Biol 103:726-30
Istfan, Nawfal W; Chen, Zhi-Yi; Rex, Sybille (2002) Fish oil slows S phase progression and may cause upstream shift of DHFR replication origin ori-beta in CHO cells. Am J Physiol Cell Physiol 283:C1009-24
Rex, Sybille; Kukuruzinska, Maria A; Istfan, Nawfal W (2002) Inhibition of DNA replication by fish oil-treated cytoplasm is counteracted by fish oil-treated nuclear extract. Am J Physiol Cell Physiol 283:C1365-75
Chen, Z Y; Istfan, N W (2001) Docosahexaenoic acid, a major constituent of fish oil diets, prevents activation of cyclin-dependent kinases and S-phase entry by serum stimulation in HT-29 cells. Prostaglandins Leukot Essent Fatty Acids 64:67-73
Chen, Z Y; Istfan, N W (2000) Docosahexaenoic acid is a potent inducer of apoptosis in HT-29 colon cancer cells. Prostaglandins Leukot Essent Fatty Acids 63:301-8
Istfan, N W; Wan, J M; Bistrian, B R et al. (1994) DNA replication time accounts for tumor growth variation induced by dietary fat in a breast carcinoma model. Cancer Lett 86:177-86
Wan, J M; Bistrian, B R; Figoni, M A et al. (1994) Influence of interleukin-2 infusion on cell cycle kinetics in the Walker-256 carcinosarcoma. J Leukoc Biol 55:241-7
Ling, P R; Bistrian, B R; Mendez, B et al. (1994) Effects of systemic infusions of endotoxin, tumor necrosis factor, and interleukin-1 on glucose metabolism in the rat: relationship to endogenous glucose production and peripheral tissue glucose uptake. Metabolism 43:279-84
Wan, J M; Fogt, F; Bistrian, B R et al. (1993) Evaluation of antitumor effect of tumor necrosis factor in terms of protein metabolism and cell cycle kinetics. Am J Physiol 265:C365-74
Ye, S L; Istfan, N W; Driscoll, D F et al. (1992) Tumor and host response to arginine and branched chain amino acid-enriched total parenteral nutrition. A study involving Walker 256 carcinosarcoma-bearing rats. Cancer 69:261-70

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