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Biomedical subjects

D A Tice

Publications and source records attributed to D A Tice.

At least 19 recordsLinked to original sources
PubMed2001

Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase 1epsilon.

Axin and the adenomatous polyposis coli protein (APC) interact to down-regulate the proto-oncogene beta-catenin. We show that transposition of an axin-binding site can confer beta-catenin regulatory activity to a fragment of APC normally lacking this activity. The fragment containing the axin-binding site also underwent hyperphosphorylation when coexpressed with axin. The phosphorylation did not require glycogen synthase kinase 3beta but instead required casein kinase 1epsilon, which bound directly to axin. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin. These results suggest that the axin-dependent phosphorylation of APC is mediated in part by CKIepsilon and is involved in the regulation of APC function.

Adenomatous Polyposis Coli Protein↗
PubMed2001

Overexpression of the retinoic acid-responsive gene Stra6 in human cancers and its synergistic induction by Wnt-1 and retinoic acid.

Genetic defects in the Wnt-1 signaling pathway contribute to human tumor progression and are especially prevalent in colorectal cancer. We screened mouse C57MG cells to isolate mRNAs induced by Wnt-1 and identified Stra6, an mRNA known to be up-regulated by retinoic acid. Up-regulation of Stra6 mRNA was also observed in hyperplastic mammary tissue and mammary gland tumors from transgenic mice expressing Wnt-1 and in human tumors that frequently harbor defects in Wnt-1 signaling. Stimulation of C57MG cells with retinoic acid plus Wnt-1 resulted in expression of Stra6 transcript to levels greatly exceeding that observed with either stimulus alone. This synergy could be explained in part by the up-regulation of retinoic acid receptor-gamma that was observed in response to Wnt-1 signaling. Accordingly, treatment of human colorectal cancer cell lines with retinoic acid resulted in the up-regulation of Stra6 mRNA and accumulation of Stra6 protein at the cell membrane. The data support a model in which Wnt-1 signaling synergizes with retinoids to activate retinoic acid receptor-gamma-responsive genes in human cancers.

Adenocarcinoma↗
PubMed2001

Src family kinases and HER2 interactions in human breast cancer cell growth and survival.

Evidence from murine fibroblast models and human breast cancer cells indicates that c-Src and human EGF receptor (HER1) synergize to enhance neoplastic growth of mammary epithelial cells. To investigate whether interactions between c-Src and other HER family members may also play a role in breast tumor progression, we characterized 13 human breast carcinoma cell lines and 13 tumor samples for expression of HER family members and c-Src and examined a subset of the cell lines for Src-dependent, heregulin (HRG)-augmented, anchorage-dependent and independent growth. By immunoblotting, we found that all cell lines overexpressed one or more HER family member, and 60% overexpressed c-Src. Seventy-five per cent of the tumor tissues overexpressed HER2, while 64% overexpressed c-Src. Colony formation in soft agar was enhanced by HRG in three of five cell lines tested, a response that correlated with the presence of a c-Src/HER2 heterocomplex. This result suggests that HRG may act through both HER2 and c-Src to facilitate anchorage-independent growth. In contrast, HRG had little effect on anchorage-dependent growth in any of the cell lines tested. PP1, a Src family kinase inhibitor, reduced or ablated HRG-dependent and independent soft agar growth or anchorage dependent growth, and triggered apoptosis in all cell lines tested. The apoptotic effect of PP1 could be partially or completely reversed by HRG, depending on the cell line. These results suggest that while Src family kinases may cooperate with HRG to promote the survival and growth of human breast tumor cells, they also function independently of HER2/HRG in these processes.

Breast Neoplasms↗
PubMed1999

c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function.

Accumulating evidence indicates that interactions between the epidermal growth factor receptor (EGFR) and the nonreceptor tyrosine kinase c-Src may contribute to an aggressive phenotype in multiple human tumors. Previous work from our laboratory demonstrated that murine fibroblasts which overexpress both these tyrosine kinases display synergistic increases in DNA synthesis, soft agar growth, and tumor formation in nude mice, and increased phosphorylation of the receptor substrates Shc and phospholipase gamma as compared with single overexpressors. These parameters correlated with the ability of c-Src and EGFR to form an EGF-dependent heterocomplex in vivo. Here we provide evidence that association between c-Src and EGFR can occur directly, as shown by receptor overlay experiments, and that it results in the appearance of two novel tyrosine phosphorylations on the receptor that are seen both in vitro and in vivo following EGF stimulation. Edman degradation analyses and co-migration of synthetic peptides with EGFR-derived tryptic phosphopeptides identify these sites as Tyr845 and Tyr1101. Tyr1101 lies within the carboxyl-terminal region of the EGFR among sites of receptor autophosphorylation, while Tyr845 resides in the catalytic domain, in a position analogous to Tyr416 of c-Src. Phosphorylation of Tyr416 and homologous residues in other tyrosine kinase receptors has been shown to be required for or to increase catalytic activity, suggesting that c-Src can influence EGFR activity by mediating phosphorylation of Tyr845. Indeed, EGF-induced phosphorylation of Tyr845 was increased in MDA468 human breast cancer cells engineered to overexpress c-Src as compared with parental MDA 468 cells. Furthermore, transient expression of a Y845F variant EGFR in murine fibroblasts resulted in an ablation of EGF-induced DNA synthesis to nonstimulated levels. Together, these data support the hypothesis that c-Src-mediated phosphorylation of EGFR Tyr845 is involved in regulation of receptor function, as well as in tumor progression.

Amino Acid Sequence↗
PubMed1999

Mechanism of biological synergy between cellular Src and epidermal growth factor receptor.

Overexpression of both cellular Src (c-Src) and the epidermal growth factor receptor (EGFR) occurs in many of the same human tumors, suggesting that they may functionally interact and contribute to the progression of cancer. Indeed, in murine fibroblasts, overexpression of c-Src has been shown to potentiate the mitogenic and tumorigenic capacity of the overexpressed EGFR. Potentiation correlated with the ability of c-Src to physically associate with the activated EGFR and the appearance of two unique in vivo phosphorylations on the receptor (Tyr-845 and Tyr-1101). Using stable cell lines of C3H10T1/2 murine fibroblasts that contain kinase-deficient (K-) c-Src and overexpressed wild-type EGFR, we show that the kinase activity of c-Src is required for both the biological synergy with the receptor and the phosphorylations on the receptor, but not for the association of c-Src with the receptor. In transient transfection assays, not only epidermal growth factor but also serum- and lysophosphatidic acid-induced DNA synthesis was ablated in a dominant-negative fashion by a Y845F mutant of the EGFR, indicating that c-Src-induced phosphorylation of Y845 is critical for the mitogenic response to both the EGFR and a G protein-coupled receptor (lysophosphatidic acid receptor). Unexpectedly, the Y845F mutant EGFR was found to retain its full kinase activity and its ability to activate the adapter protein SHC and extracellular signal-regulated kinase ERK2 in response to EGF, demonstrating that the mitogenic pathway involving phosphorylation of Y845 is independent of ERK2-activation. The application of these findings to the development of novel therapeutics for human cancers that overexpress c-Src and EGFR is discussed.

Amino Acid Substitution↗
PubMed1997

Overexpression of cellular Src in fibroblasts enhances endocytic internalization of epidermal growth factor receptor.

Previous studies have demonstrated a requirement for the nonreceptor tyrosine kinase, cellular Src (c-Src), in epidermal growth factor (EGF)-induced mitogenesis and a synergistic interaction between c-Src and EGF receptor (EGFR) in tumorigenesis. Although endocytic internalization of EGFR may be thought to attenuate EGF-stimulated signaling, recent evidence suggests that signaling through Ras can be amplified by repeated encounters of endosome-localized, receptor. Shc.Grb2.Sos complexes with the plasma membrane, where Ras resides almost exclusively. Based on these reports, we examined EGFR trafficking behavior in a set of single and double c-Src/EGFR C3H10T1/2 overexpressors to determine if c-Src affects basal receptor half-life, ligand-induced internalization, and/or recycling. Our results show that overexpression of c-Src causes no change in EGFR half-life but does produce an increase in the internalization rate constant of EGF.EGFR complexes when the endocytic apparatus is not stoichiometrically saturated; this effect of c-Src on EGFR endocytosis is negligible at high receptor occupancy in cells overexpressing the receptor. In neither case are EGFR recycling rate constants affected by c-Src. These data indicate a functional role for c-Src in receptor internalization, which in turn could alter some aspects of EGFR signaling related to mitogenesis and tumorigenesis.

Animals↗
PubMed1978

Complications due to cloth wear in cloth-covered Starr-Edwards aortic and mitral valve prostheses--and their management.

Five cases of complications due to cloth wear in cloth-covered composite-seat Starr-Edwards aortic and mitral valvular prostheses are described. The complications of cloth wear were recurrent systemic emboli in three patients, two with aortic and one with mitral prosthesis, and severe hemolytic anemia in two patients with aortic prosthesis. The over-all incidence of clinically significant complications due to cloth wear in aortic and mitral valve prosthesis was 2.5 per cent. The diagnosis of cloth wear is impossible before reoperation and it was made by exclusion of other causes of recurrent transient cerebral ischemic attacks or systemic emboli and by exclusion of other causes of hemolytic anemia. Clinical and laboratory findings suggestive of cloth wear are described. Aggressive management of complications of cloth wear by reoperation is likely to prevent disabling or lethal consequences. Porcine xenograft aortic and mitral bioprostheses were used in these patients to replace the cloth-covered valvular prostheses. The symptoms due to cloth wear were abolished in all patients by reoperation, and all patients are off anticoagulants postoperatively. The operative mortality rate for reoperation in this small group of patients was zero.

Adult↗
PubMed1977

Fell tube insertion after orthograde dilatation of malignant esophageal obstruction: palliation and morbidity.

Twenty-eight patients with malignant esophageal obstruction had palliative treatment using the Fell endoesophageal tube. The usual plan for these patients, irradiation followed by resection, was not followed because of the presence of tracheoesophageal fistula, celiac or hepatic metastases, or marked debilitation which precluded major operation. Palliation was obtained in ten patients who were discharged in a mean of 16.5 days with the ability to swallow liquids or pureed or ground foods and had a mean survival of 116 days. There was a high incidence of tube-related symptoms in all patients, and increased dysphagia, tube regurgitation, and difficulties in initiating swallowing were noted in patients with lesions above 24 cm from the incisors. The high incidence of postoperative ocmplications was responsible for the poor palliation and low survival in the remaining 18 patients who had a mean survival of 41 days. It was concluded that orthograde dilatation or forced seating of the prosthesis through a malignant esophageal obstruction carries a significant risk of perforation of the esophagus which, if it occurs, negates the palliative aspects of the procedure, increases hospitalization, and decreases survival. It is recommended that this procedure be used selectively in patients not otherwise amenable to resectional therapy with lesions beyond 24 cm from the incisors.

Aged↗
PubMed1977

Infective endocarditis. An analysis of 54 surgically treated patients.

One hundred seventy-seven patients were admitted to the New York University Medical Center from 1970 through 1975 with infective endocarditis. Fifty-four of these patients required surgical treatment. The over-all mortality rate was 28 per cent. Two thirds of the deaths were early (10 patients) and one third late (5 patients). The mortality rate was 90 per cent in 10 patients treated for 4 to 6 weeks in whom the infection was uncontrolled and the clinical condition was deteriorating. However of the 12 patients with uncontrolled infection who were operated upon promptly within 10 days, 83 per cent survived. The fact that fungal and gram-negative infections responded poorly to medical therapy suggests the need for prompt, early surgical intervention. The mortality rate in the 32 patients operated upon in whom the infection was controlled was 12.5 per cent. It is our conclusion that all patients with infective endocarditis who develop progressive congestive failure, recurrent embolization, or progressive sepsis, despite treatment, shold have prompt valve replacement within 7 days of the institution of appropriate antimicrobial therapy.

Adult↗
PubMed1976

Operative risk in patients with previous coronary artery bypass.

The records of 141 patients who had had coronary artery bypass and myocardial revascularization were reviewed. Fifteen percent (20) of the patients in this series required a surgical procedure from three months to five years following coronary artery bypass. Twelve percent (16) of these patients had elective operations, and 3% had emergency operations. In the elective group there were no deaths. One patient had a proved myocardial infarction, and three patients had transient arrhythmias with no changes in myocardial enzymes. In the emergency group there was one death, from sepsis following splenectomy for splenic abscess. Although the series is small, the data suggest that patients with coronary artery disease who have had myocardial revascularization are acceptable risks for elective and emergency operations. Whether the risk is lower in this group as compared to that in other patients with coronary disease who have not had bypass surgery has not been demonstrated.

Coronary Artery Bypass↗
PubMed1976

Coronary artery bypass with freeze-preserved saphenous vein allografts.

Over the past 5 years, 13 patients had coronary artery bypass performed with freeze-preserved saphenous vein allografts. There were no operative deaths or significant morbidity. Six patients were studied postoperatively at 42, 37, 10, 7, 5, and 1 months. Six of 8 grafts were patent with good flow. There were four late deaths; two of these occurred in patients who had concomitant resection of a ventricular aneurysm. Of the 9 surviving patients, 6 (6/9) are asymptomatic and 2 (2/9) have occasional chest pains; the condition of 1 patient (1/9) is unchanged. This experience suggests that free-preserved saphenous vein allografts may be used successfully for coronary bypass when autologous veins and internal mammary arteries are unavailable or insufficient for multiple bypass.

Aged↗
PubMed1975

Esophagogastrostomy. Analysis of 55 cases.

At the New York University Medical Center from January, 1969, through December, 1973, esophagogastrostomies were performed in 56 patients. In 30 (Group A), fundoplications were combined with the esophagogastrostomies; in the other 26 (Group B), esophagogastrostomies only were performed. These two groups have been compared in an effort to determine the effectiveness of fundoplication in preventing gastric reflux following esophagogastrostomy. The operative mortality rate (10 per cent) and the 3 year survival rate (20 per cent) were approximately equal in the two groups. Clinical evidence of reflux was noted in 10 per cent of Group A and 47 per cent of Group B patients, while complications of reflux were noted in 5 per cent of Group A and in 33 per cent of Group B patients. The results of the present study suggest that fundoplication, while not prolonging survival, does prevent the symptoms and complications of gastric reflux and improves the quality of survival in these unfortunate patients. This leads us to recommend the routine use of fundoplication with esophagogastrostomy in patients with carcinoma of the esophagus and gastric cardia.

Adenocarcinoma↗