Homologs of Drosophila Mad function as downstream mediators of the receptors for transforming growth factor  (TGF-)-related factors. Two homologs, the receptor-associated Smad3 and the tumor suppressor Smad4/DPC4, synergize to induce ligand-independent TGF- activities and are essential mediators of the natural TGF- response. We now show that Smad3 and Smad4 associate in homomeric and heteromeric interactions, as assessed by yeast two-hybrid and coimmunoprecipitation analyses. Heteromeric interactions are mediated through the conserved C-terminal domains of Smad3 and Smad4. In Smad3, the homomeric interaction is mediated by the same domain. In contrast, the homomeric association of Smad4 requires both the N-terminal domain and the C-terminal domain, which by itself does not homomerize. Mutations that have been associated with impaired Mad activity in Drosophila or decreased tumor suppressor activity of Smad4/ DPC4 in pancreas cancer, including a short C-terminal truncation and two point mutations in the conserved C-terminal domains, impair the ability of Smad3 and Smad4 to undergo homo-and heteromeric associations. Analyses of the biological activity of Smad3 and Smad4 and their mutants show that full signaling activity correlates with their ability to undergo efficient homo-and heteromeric interactions. Mutations that interfere with these interactions result in decreased signaling activity. Finally, we evaluated the ability of Smad3 or Smad4 to induce transcriptional activation in yeast. These results correlate the ability of individual Smads to homomerize with transcriptional activation and additionally with their biological activity in mammalian cells.Transforming growth factor  (TGF-)-related factors play important regulatory roles in cell differentiation and proliferation and in tissue morphogenesis in animals ranging from flies and nematodes to mammals (12,16). Among the many members of the TGF- superfamily, which include activins and bone morphogenetic proteins (BMPs) (12, 16), TGF-1 is considered the prototype factor to characterize the various cellular responses and the mechanism of receptor signaling. The growth-inhibitory effect of TGF- in a variety of cell types, such as epithelial cells, and its ability to induce gene expression that leads to increased extracellular matrix deposition have been best characterized (5). Similarly to BMP-2/4 and activin, TGF- exerts its activities through two types of cell surface serine/threonine kinase receptors, type II and type I receptors. The type II and type I receptors have the ability to form a heterotetrameric complex, consisting of two type II and two type I receptors, and this complex is thought to represent the fully functional receptor complex that mediates TGF- signaling following ligand binding. In this tetrameric complex, the constitutively active type II receptors phosphorylate the type I receptor cytoplasmic domains, and this phosphorylation is required for activation of the signaling pathways leading to the TGF- response (4,18,22).The down...
We explored the relationship of RAS gene mutations with epidemiologic and cytogenetic factors in a case series of children with leukemia. Diagnostic bone marrow samples from 191 incident leukemia cases from the Northern California Childhood Leukemia Study were typed for NRAS and KRAS codon 12 and 13 mutations. A total of 38 cases (20%) harbored RAS mutations. Among the 142 B-cell acute lymphoblastic leukemia (ALL) cases, RAS mutations were more common among Hispanic children (P ¼ 0.11) or children born to mothers o30 years (P ¼ 0.007). Those with hyperdiploidy at diagnosis (450 chromosomes) had the highest rates of RAS mutation (P ¼ 0.02). A multivariable model confirmed the significant associations between RAS mutation and both maternal age and hyperdiploidy. Interestingly, smoking of the father in the 3 months prior to pregnancy was reported less frequently among hyperdiploid leukemia patients than among those without hyperdiploidy (P ¼ 0.02). The data suggest that RAS and high hyperdiploidy may be cooperative genetic events to produce the leukemia subtype; and furthermore, that maternal age and paternal preconception smoking or other factors associated with these parameters are critical in the etiology of subtypes of childhood leukemia.
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