Gerald H. Thomsen

MADR2 Maps to 18q21 and Encodes a TGFβ–Regulated MAD–Related Protein That Is Functionally Mutated in Colorectal Carcinoma

The MAD-related (MADR) family of proteins are essential components in the signaling pathways of serine/threonine kinase receptors for the transforming growth factor beta (TGFbeta) superfamily. We demonstrate that MADR2 is specifically regulated by TGFbeta and not bone morphogenetic proteins. The gene for MADR2 was found to reside on chromosome 18q21, near DPC4, another MADR protein implicated in pancreatic cancer. Mutational analysis of MADR2 in sporadic tumors identified four missense mutations in colorectal carcinomas, two of which display a loss of heterozygosity. Biochemical and functional analysis of three of these demonstrates that the mutations are inactivating. These findings suggest that MADR2 is a tumor suppressor and that mutations acquired in colorectal carcinomas may function to disrupt TGFbeta signaling.

Nomenclature: Vertebrate Mediators of TGFβ Family Signals

Anita B. Roberts,10 Jim Smith,11 Gerald H. Thomsen,14 Nomenclature: Vertebrate Bert Vogelstein,7,12 and Xiao-Fan Wang,13 Mediators of TGFb Family 1 Departments of Growth and Development, and Anatomy, Programs of Cell and Developmental Biology Signals University of California, San Francisco San Francisco, California 94143-0640 2 Department of Cellular Developmental Biology The Mad (mothers against decapentaplegic) gene in Harvard University Drosophila and the related Sma genes in Caenorhabditis Cambridge, Massachusetts 02138-2019 elegans have been implicated in signal transduction by 3 Department of Molecular and Cell Biology factors of the TGFb family (Sekelski et al., 1995; Savage Division of Biochemistry and Molecular Biology et al., 1996). Related genes have been identified recently University of California, Berkeley in vertebratesand shown to mediateTGFb family signals Berkeley, California 94720-3204 in these organisms as well. To date, there are five family 4 Ludwig Institute for Cancer Research members described as full length protein sequences S75124 Uppsala, Sweden in human, mouse, and/or Xenopus. Because of their 5 Department of Oncology diversity and simultaneous identification in different labJohn Hopkins School of Medicine oratories, the Mad-related products in vertebrates have Baltimore, Maryland 21205-2196 received different names. In order to facilitate future 6 Department of Cell Biology work and the dissemination of information in this area, Memorial Sloan-Kettering Cancer Center we propose to unify the nomenclature of the vertebrate New York, New York 10021 genes and their products by referring to them as 7 Howard Hughes Medical Institute “Smad.” This term, a merger of Sma and Mad, differenti8 Developmental Biology Programme ates these proteins from unrelated gene products preEuropean Molecular Biology Laboratory viously called Mad. We propose that each individual 69117 Heidelberg, Germany family member be designated as follows. 9 Waksman Institute Department of Molecular Biology and Biochemistry Smad1 and Cancer Institute of New Jersey GenBank accession numbers are U54826, U57456, Rutgers University U58992, U59912, U59423, U58834, and L77888. Smad1 Piscataway, New Jersey 08855-0759 has been previously referred to as Madr1, bsp1, 10 National Cancer Institute Dwarfin-A, Xmad, Xmad1, and JV4-1. National Institute of Health Bethesda, Maryland 20892-5055 Smad2 11 National Institute for Medical Research GenBank accession numbers are U59911, U60530, The Ridgeway, Mill Hille U65019, U68018 and L77885. Smad2 has been preLondon NW7 1AA, England viously referred to as Madr2, hMAD-2, Xmad2, and 12 The Johns Hopkins Oncology Center JV18-1. Baltimore, Maryland 21231 13 Department of Pharmacology Duke University Medical Center Smad3 Durham, North Carolina 27710 GenBank accession number isU68019. Smad3 has been 14 Department of Biochemistry and Cell Biology previously referred to as hMAD-3. Institute for Cell and Developmental Biology State University of New York Smad4 also referred to in the human as DPC4 (deleted Stony Brook, New York 11794-5215 in pancreatic carcinoma). GenBank accession number isU44378. Smad4 has been References previously referred to as Xmad4.

Ventral mesoderm induction and patterning by bone morphogenetic protein heterodimers in Xenopus embryos

Bone morphogenetic proteins (BMPs) perform diverse functions in vertebrate development. Here we demonstrate that the heterodimeric BMP-4/7 protein directly induces ventral mesoderm and blood in Xenopus animal caps, and BMP-2/7 heterodimers may function similarly. We also provide indirect evidence that BMP heterodimers function in embryos, using assays with dominant-negative BMP ligands. Homodimeric BMP-2 and BMP-4 proteins do not induce mesoderm, but they ventralize mesoderm induction by activin. In contrast, BMP-7 protein interferes with mesoderm induction by activin, but BMP-7 stimulates ventral mesoderm induction by the heterodimer, BMP-4/7. This novel property of BMP-7 distinguishes it from other BMPs. BMP-7 may therefore function in early embryogenesis to antagonize activin signals and potentiate BMP signals. We propose that BMP heterodimers convey signals for ventral mesoderm induction and patterning in Xenopus development.

Transport of DNA into the nuclei of xenopus oocytes by a modified VirE2 protein of Agrobacterium.

We used Agrobacterium T-DNA nuclear transport to examine the specificity of nuclear targeting between plants and animals and the nuclear import of DNA by a specialized transport protein. Two karyophilic Agrobacterium virulence (Vir) proteins, VirD2 and VirE2, which presumably associate with the transported T-DNA and function in many plant species, were microinjected into Drosophila embryos and Xenopus oocytes. In both animal systems, VirD2 localized to the cell nuclei and VirE2 remained exclusively cytoplasmic, suggesting that VirE2 nuclear localization signals may be plant specific. Repositioning one amino acid residue within VirE2 nuclear localization signals enabled them to function in animal cells. The modified VirE2 protein bound DNA and actively transported it into the nuclei of Xenopus oocytes. These observations suggest a functional difference in nuclear import between animals and plants and show that DNA can be transported into the cell nucleus via a protein-specific pathway.