NASA Scientific and Technical Aerospace Reports
NASA Scientific and Technical Aerospace Reports
NASA Scientific and Technical Aerospace Reports
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observations that cells expressing differing levels of KSR1 show variable actin-cytoskeletal organization, cell-cell adhesion,<br />
<strong>and</strong> anchorage to the extracellular matrix. These data suggest that the scaffold protein KSR1 is intimately involved in the<br />
coordination or control of cell fate.<br />
DTIC<br />
Cancer; Cells (Biology); Enzymes; Mammary Gl<strong>and</strong>s; Phosphorus<br />
20040111733 Manitoba Univ., Winnipeg, Manitoba<br />
Interaction Between Estrogen Receptor Beta <strong>and</strong> the Transforming Growth Factor Beta Signaling Cascade in Human<br />
Breast Tissue<br />
Cherlet, Tracy C.; Murphy, Leigh C.; Jul. 2003; 19 pp.; In English<br />
Contract(s)/Grant(s): DAMD17-01-1-0307<br />
Report No.(s): AD-A425903; No Copyright; Avail: CASI; A03, Hardcopy<br />
Recent evidence has suggested that cross-talk between the TCFbeta <strong>and</strong> ER signaling pathways exist. Data from our<br />
laboratory suggests that although a physical interaction between ER <strong>and</strong> Smad3, a downstream signaling protein of the<br />
TGFbeta pathway, does not exist, a functional interaction is present. ERalpha <strong>and</strong> ERbeta inhibit Smad3 transcription on the<br />
TGFbeta reporter plasmid p3TP-lux in a lig<strong>and</strong>-dependent manner <strong>and</strong> this inhibition may be suppressed <strong>and</strong> subsequently<br />
reversed by the anti-estrogens 4-OH-tamoxifen <strong>and</strong> ICI 182,780. As both ERalpha <strong>and</strong> Smad3 interact with members of the<br />
Apl family <strong>and</strong> since the P3TP-lux promoter has three Apl binding sites, we next sought to examine whether Apl factors may<br />
be limiting factors in Smad3 transcription on p3TP-lux. Results suggest that overexpression of c-Jun but not c-Fos was able<br />
to reverse the effect of ERalpha on Smad3 transcription in Cosl cells. Our results suggest that Apl factors may be important<br />
in the regulation of TGFbeta signaling by ER. Experiments are currently underway to determine if these observations are<br />
relevant in a breast tumor cell model.<br />
DTIC<br />
Cancer; Cells (Biology); Estrogens; Mammary Gl<strong>and</strong>s; Receptors (Physiology)<br />
20040111734 Pennsylvania Univ., Philadelphia, PA<br />
Targeting of Drugs to ICAM for Treatment of Acute Lung Injury<br />
Muzykantov, Vladimir; Apr. 2004; 116 pp.; In English<br />
Contract(s)/Grant(s): DAMD17-02-1-0197<br />
Report No.(s): AD-A425905; No Copyright; Avail: CASI; A06, Hardcopy<br />
In the second year, we characterized intracellular traffic <strong>and</strong> final destination of anti-CAM conjugates in endothelial cells<br />
(EC) <strong>and</strong> found that CAM-mediated endocytosis initiates an unusually slow vesicular traffic that delivers conjugates to<br />
lysosomes several hours after internalization. Further, auxiliary drugs that regulate these processes can be utilized for<br />
prolongation of therapeutic duration of internalized conjugates. We characterized a series of in-house models of human ALI<br />
(injection of anti-TM/GOX <strong>and</strong> hyperoxia in mice), studied dynamics <strong>and</strong> role of EC cell adhesion molecules <strong>and</strong> leukocytes<br />
in these models <strong>and</strong> developed a new, clinically relevant <strong>and</strong> reliable model of ALI, based on combined treatment with<br />
anti-TM/GOX <strong>and</strong> hyperoxia. We synthesized anti- CAM/ SOD conjugate with proper targeting size (^200 nm), enzymatic<br />
activity <strong>and</strong> affinity to SC <strong>and</strong> documented that it accumulates in the pulmonary vasculature after intravenous injection, thus<br />
satisfying main requirements for subsequent testing in animal models of ALI. In vitro <strong>and</strong> in vivo fibrinolysis studies have<br />
been employed in order to select the optimal c<strong>and</strong>idate fibrinolytic (a novel tPA derivative, Tenektase) for targeting to<br />
endothelial CAM. Design <strong>and</strong> production of optimized affinity carriers for this purpose is in progress.<br />
DTIC<br />
Drugs; Endothelium; Injuries; Lungs<br />
20040111736 Iowa Univ., Iowa City, IA<br />
Regulatory Pathways Involved in Heregulin-Induced Proliferation <strong>and</strong> Differentiation of Human Breast Cancer Cells<br />
Lee, Nam; Kol<strong>and</strong>, John; Apr. 2004; 13 pp.; In English; Original contains color illustrations<br />
Contract(s)/Grant(s): DAMD17-98-1-8199<br />
Report No.(s): AD-A425907; No Copyright; Avail: CASI; A03, Hardcopy<br />
The polypeptide heregulin has been shown to reverse the transformed phenotype of certain cultured breast cancer cell<br />
lines <strong>and</strong> convert them to more normal, milk- producing cells. In contrast, heregulin has been reported to induce proliferation<br />
of other breast cancer cell lines. These diverse effects of heregulin are mediated by receptors in the ErbB/HER family, which<br />
function as coreceptor complexes. We first attempted to determine how the different signaling pathways activated by ErbB<br />
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