Biomedical subjects

Clifford M Takemoto

Publications and source records attributed to Clifford M Takemoto.

3 recordsLinked to original sources

PubMed2007

Distinct and shared transcriptomes are regulated by microphthalmia-associated transcription factor isoforms in mast cells.

The Microphthalmia-associated transcription factor (Mitf) is an essential basic helix-loop-helix leucine zipper transcription factor for mast cell development. Mice deficient in Mitf harbor a severe mast cell deficiency, and Mitf-mutant mast cells cultured ex vivo display a number of functional defects. Therefore, an understanding of the genetic program regulated by Mitf may provide important insights into mast cell differentiation. Multiple, distinct isoforms of Mitf have been identified in a variety of cell types; we found that Mitf-a, Mitf-e, and Mitf-mc were the major isoforms expressed in mast cells. To determine the physiologic function of Mitf in mast cells, we restored expression of these isoforms in primary mast cells from Mitf(-/-) mice. We found that these isoforms restored granular morphology and integrin-mediated migration. By microarray analysis, proteases, signaling molecules, cell surface receptor, and transporters comprised the largest groups of genes up-regulated by all isoforms. Furthermore, we found that isoforms also regulated distinct genes sets, suggesting separable biological activities. This work defines the transcriptome regulated by Mitf in mast cells and supports its role as master regulator of mast cell differentiation. Expression of multiple isoforms of this transcription factor may provide for redundancy of biological activities while also allowing diversity of function.

Animals↗

PubMed2007

Acquired coagulation factor inhibitors in children after topical bovine thrombin exposure.

Acquired inhibitors of coagulation factors, particularly to factor V (FV) and thrombin, after topical bovine thrombin exposure may result in clinically important coagulopathies. While bovine thrombin is commonly used in pediatric patients for surgical hemostasis, the reported cases of acquired inhibitors in children are few. We report two cases of children who developed factor inhibitors after bovine thrombin exposure. One child developed a FV inhibitor at 3 months of age after exposure to bovine thrombin during cardiac surgery. The inhibitor resolved with intravenous immunoglobulin (IVIG) and steroids. The other child developed concomitant FV and bovine thrombin inhibitors after cardiac surgery at age 11 years. The presence of these inhibitors complicated post-operative anti-coagulation management, but the inhibitors were transient. In addition to these two cases, we identified all the pediatric patients with bovine thrombin-induced inhibitors who were reported in the world's literature, and reviewed their clinical characteristics. These cases underscore the fact that bovine thrombin can be antigenic in infants and children and can result in significant coagulopathies.

Administration, Topical↗

PubMed2002

The identification and functional characterization of a novel mast cell isoform of the microphthalmia-associated transcription factor.

The microphthalmia-associated transcription factor (Mitf) is critical for mast cell development based on the severe mast cell deficiency seen in Mitf mutant mice. Mitf also is important for the development of melanocytes, osteoclasts, and retinal pigment epithelium. The lineage-restricted phenotypes of Mitf mutations correlate with tissue-restricted expression of Mitf, a feature due in part to the presence of several distinct Mitf isoforms. We report the identification and characterization of a novel mast cell isoform, Mitf-mc. This isoform arises from alternative splicing of a novel 5'-exon onto the common body of the gene and is predicted to encode a unique 43-amino acid sequence at its amino terminus. It is specifically expressed in mast cells. The mast cell isoform functions differently from the melanocyte isoform in its ability to activate cell type-specific Mitf gene targets. Mitf-mc functions only on a mast cell target promoter and fails to activate a melanocyte target promoter despite binding to its E-box element. Moreover, Mitf-mc heterodimerizes with a closely related transcription factor, Tfe3, and dominantly inhibits the ability of Tfe3 to transactivate a melanocyte-specific promoter. These studies identify a new isoform of Mitf with tissue-specific features that may underlie key aspects of the mast cell phenotype of Mitf mutations.

Amino Acid Sequence↗