Biomedical subjects

Warren S Pear

Publications and source records attributed to Warren S Pear.

43 records · Page 3Linked to original sources

PubMed2002

The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl.

The bcr/abl fusion in chronic myelogenous leukemia (CML) creates a chimeric tyrosine kinase with dramatically different properties than intact c-abl. In P210 bcr/abl, the bcr portion includes a coiled-coil oligomerization domain (amino acids 1-63) and a grb2-binding site at tyrosine 177 (Tyr177) that are critical for fibroblast transformation, but give variable results in other cell lines. To investigate the role of the coiled-coil domain and Tyr177 in promoting CML, 4 P210 bcr/abl-derived mutants containing different bcr domains fused to abl were constructed. All 4 mutants, Delta(1-63) bcr/abl, (1-63) bcr/abl, Tyr177Phe bcr/abl, and (1-210) bcr/abl exhibited elevated tyrosine kinase activity and conferred factor-independent growth in cell lines. In contrast, differences in the transforming potential of the 4 mutants occurred in our mouse model, in which all mice receiving P210 bcr/abl-expressing bone marrow cells exclusively develop a myeloproliferative disease (MPD) resembling human CML. Of the 4 mutants assayed, only 1-210 bcr/abl, containing both the coiled-coil domain and Tyr177, induced MPD. Unlike full-length P210, this mutant also caused a simultaneous B-cell acute lymphocytic leukemia (ALL). The other 3 mutants, (1-63) bcr/abl, Tyr177Phe bcr/abl, and Delta(1-63) bcr/abl, failed to induce an MPD but instead caused T-cell ALL. These results show that both the bcr coiled-coil domain and Tyr177 are required for MPD induction by bcr/abl and provide the basis for investigating downstream signaling pathways that lead to CML.

Animals↗

PubMed2002

Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling.

Mice deficient in the adaptor Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) exhibit a bleeding disorder and lack T cells. Linker for activation of T cells (LAT)-deficient mice exhibit a similar T cell phenotype, but show no signs of hemorrhage. Both SLP-76 and LAT are important for optimal platelet activation downstream of the collagen receptor, GPVI. In addition, SLP-76 is involved in signaling mediated by integrin alphaIIbbeta3. Because SLP-76 and LAT function coordinately in T cell signal transduction, yet their roles appear to differ in hemostasis, we investigated in detail the functional consequences of SLP-76 and LAT deficiencies in platelets. Previously we have shown that LAT(-/-) platelets exhibit defective responses to the GPVI-specific agonist, collagen-related peptide (CRP). Consistent with this, we find that surface expression of P-selectin in response to high concentrations of GPVI ligands is reduced in both LAT- and SLP-76-deficient platelets. However, platelets from LAT(-/-) mice, but not SLP-76(-/-) mice, aggregate normally in response to high concentrations of collagen and convulxin. Additionally, unlike SLP-76, LAT is not tyrosine phosphorylated after fibrinogen binding to integrin alphaIIbbeta3, and collagen-stimulated platelets deficient in LAT spread normally on fibrinogen-coated surfaces. Together, these findings indicate that while LAT and SLP-76 are equally required for signaling via the T cell antigen receptor (TCR) and pre-TCR, platelet activation downstream of GPVI and alphaIIbbeta3 shows a much greater dependency on SLP-76 than LAT.

Adaptor Proteins, Signal Transducing↗

PubMed2002

An invitation to T and more: notch signaling in lymphopoiesis.

Cell fate decisions in metazoans are regulated by Notch signals. During lymphoid development, Notch influences a series of cell fate decisions involving multipotent progenitors. This review focuses on current views and lingering uncertainties about Notch function in lymphoid cells.

Animals↗

PubMed2002

Deciphering the role of Notch signaling in lymphopoiesis.

Components of the Notch signaling pathway are expressed during multiple stages of lymphoid development. Consistent with its function during invertebrate development, Notch signaling is proposed to have a central role in lymphoid cell-fate specification. Recent studies show that Notch signaling is a proximal event in T-cell commitment from a common lymphoid progenitor. The role of Notch at later stages of lymphoid development is controversial, but recent data suggest models that may help clarify observations. Current studies suggest that Notch activity is cell-context dependent and interactions between Notch and other environmental receptors are integrated during cell-fate decisions. Furthermore, the requirement for precise regulation of Notch activity is evident from human and murine neoplasms in which dysregulated Notch signaling leads to T-cell leukemia. Future studies that identify the stages of lymphoid development where Notch signaling is physiologically active and the exact targets of Notch signaling that are relevant to lymphopoiesis should significantly improve our understanding of Notch function in T- and B-cell development.

Animals↗

PubMed2002

Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1.

Notch1 signaling drives T cell development at the expense of B cell development from a common precursor, an effect that is dependent on a C-terminal Notch1 transcriptional activation domain. The function of Deltex1, initially identified as a positive modulator of Notch function in a genetic screen in Drosophila, is poorly understood. We now demonstrate that, in contrast to Notch1, enforced expression of Deltex1 in hematopoietic progenitors results in B cell development at the expense of T cell development in fetal thymic organ culture and in vivo. Consistent with these effects, Deltex1 antagonizes Notch1 signaling in transcriptional reporter assays by inhibiting coactivator recruitment. These data suggest that a balance of inductive Notch1 signals and inhibitory signals mediated through Deltex1 and other modulators regulate T-B lineage commitment.

3T3 Cells↗

PubMed2002

Notch signaling in hematopoiesis and early lymphocyte development.

Notch signals regulate multiple cell fate decisions during metazoan development. During hematopoiesis, Notch affects both hematopoietic stem cells and committed progenitors. In hematopoietic stem cells, Notch signaling has the propensity to expand the stem cells, promote their self-renewal, and influence their survival. In committed progenitors, Notch signaling plays a key role in determining lymphoid cell fates. This review focuses on recent developments to understand the role of Notch signaling in early events in hematopoiesis.

Animals↗

PubMedDate not supplied

Notch signaling in cancer.

Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on differentiation, survival, and/or proliferation that are highly dependent on signal strength and cellular context. Because perturbations in the regulation of differentiation, survival, and/or proliferation underlie malignant transformation, pathophysiologic Notch signals potentially contribute to cancer development in several different ways. Notch signaling was first linked to tumorigenesis through identification of a recurrent t(7;9)(q34;q34.3) chromosomal translocation involving the human Notch1 gene that is found in a small subset of human pre-T-cell acute lymphoblastic leukemias (T-ALL).(1) Since this discovery, aberrant Notch signaling has been suggested to be involved in a wide variety of human neoplasms. In this review, we will focus on recent studies linking aberrant Notch signaling with cancer. First, we discuss various mechanisms through which Notch signaling may influence cellular transformation. Then, we critically review literature pertaining to the role of Notch signaling in several cancers, and discuss possible therapeutic targets in the Notch pathway.

Animals↗