Biomedical subjects

Timothy P Bender

Publications and source records attributed to Timothy P Bender.

4 recordsLinked to original sources

PubMed2005

c-Myb is critical for B cell development and maintenance of follicular B cells.

The c-Myb transcription factor is crucial during definitive hematopoiesis. However, the embryonic lethality of Myb traditional null mutations has precluded analysis of c-Myb function in lymphocytes. Using tissue-specific inactivation at the Myb locus, we demonstrate that loss of Myb causes a partial block during B cell development at the pro-B to pre-B cell transition, resulting in greatly decreased output of new B cells from the bone marrow. Furthermore, we demonstrate that Myb is not essential for the proliferation of splenic B cells, but that loss of c-Myb function prevents normal B cell homeostasis due to decreased splenic B cell survival. Decreased survival is accompanied by hyporesponsiveness to the B cell survival factor BLyS (also termed BAFF), decreased expression of the BLyS receptor 3 (BR3), and altered regulation of PKCdelta nuclear accumulation. Thus, c-Myb is important during multiple stages of B-lymphopoiesis.

Animals↗

PubMed2004

Critical functions for c-Myb at three checkpoints during thymocyte development.

The transcription factor c-Myb is expressed throughout T cell development in the thymus. However, little is understood about c-Myb function because of the embryonic lethality of traditional Myb-null mutations. Using tissue-specific deletion to abrogate c-Myb expression at distinct stages of T cell development, we identify three points at which c-Myb activity is required for normal T cell differentiation: transition through the double-negative 3 stage, survival of preselection CD4(+)CD8(+) thymocytes, and differentiation of CD4 thymocytes. Thus, c-Myb is essential at several stages during T cell development in the thymus.

Animals↗

PubMed2002

A nonredundant role for the adapter protein Shc in thymic T cell development.

Signaling via the pre-T cell receptor (pre-TCR) regulates survival, proliferation, allelic exclusion and differentiation of thymocytes. The role played by the adapter protein Shc in T cells has remained controversial, and its role in pre-TCR signaling has not been addressed. We examined Shc function in thymic T cell development using two genetic approaches. Cre-loxP-mediated inducible expression in transgenic mice of a phosphorylation-defective mutant of Shc impaired signaling through the pre-TCR as well as subsequent proliferation and differentiation. Conditional deletion of the Shc locus in thymocytes also affected thymic maturation at the same pre-TCR developmental stage. Thus, both Shc expression and its tyrosine phosphorylation play an essential and nonredundant role in thymic T cell development.

Adaptor Proteins, Signal Transducing↗

PubMed2002

A Myb dependent pathway maintains Friend murine erythroleukemia cells in an immature and proliferating state.

Friend murine erythroleukemia (MEL) cells are transformed erythroid precursors that are held in an immature and proliferating state but can be induced to differentiate in vivo by treatment with a variety of chemical agents such as N, N-hexamethylene bisacetamide (HMBA). To investigate the role of Myb proteins in maintaining MEL cells in an immature and proliferating state we have produced stable transfectants in the C19 MEL cell line that contain a dominant interfering Myb allele (MEnT) under the control of an inducible mouse metallothionein I promoter. When expression of MEnT protein was induced with ZnCl2, the stable transfectants differentiated with kinetics that were similar to wild type C19 MEL cells treated with HMBA, including induction of alpha-globin mRNA expression, assembly of hemoglobin and growth arrest. Expression of endogenous c-myb and c-myc was also decreased in response to MEnT. Expression of mad-1 mRNA was rapidly increased in response to expression of MEnT resulting in a shift from predominantly c-Myc/Max complexes to predominantly Mad/Max containing complexes. These results strongly suggest that C19 MEL cells are held in an immature and proliferating state by a pathway that is dependent on Myb activity.

Acetamides↗