title: BTG/Tob family members Tob1 and Tob2 inhibit proliferation of mouse embryonic stem cells via Id3 mRNA degradation.
abstract: The mammalian BTG/Tob family is a group of proteins with anti-proliferative ability, and there are six members including BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2. Among them, Tob subfamily members, specifically Tob1/Tob and Tob2, have the most extensive C-terminal regions. As previously reported, overexpression of BTG/Tob proteins is associated with the inhibition of G1 to S-phase cell cycle progression and decreased cell proliferation in a variety of cell types. Tob subfamily proteins have similar anti-proliferative effects on cell cycle progression in cultured tumor cells. An important unresolved question is whether or not they have function in rapidly proliferating cells, such as embryonic stem cells (ESCs). Tob1 and Tob2 were expressed ubiquitously in mouse ESCs (mESCs), suggesting a possible role in early embryonic development and mESCs. To address the above question and explore the possible functions of the Tob subfamily in ESCs, we established ESCs from different genotypic knockout inner cell mass (ICM). We found that Tob1(-/-), Tob2(-/-), and Tob1/2 double knockout (DKO, Tob1(-/-) & Tob2(-/-)) ESCs grew faster than wild type (WT) ESCs without losing pluripotency, and we provide a possible mechanistic explanation for these observations: Tob1 and Tob2 inhibit the cell cycle via degradation of Id3 mRNA, which is a set of directly targeted genes of BMP4 signaling in mESCs that play critical roles in the maintenance of ESC properties. Together, our data suggest that BTG/Tob family protein Tob1 and Tob2 regulation cell proliferation does not compromise the basic properties of mESCs.
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Peking University Stem Cell Research Center, China National Center for International Research, Peking University Health Science Center, Beijing 100191, China; SARI Center for Stem Cell and Nanomedicine, Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Shanghai 200120, China.
authors.forename: Yuanfan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Peking University Stem Cell Research Center, China National Center for International Research, Peking University Health Science Center, Beijing 100191, China; SARI Center for Stem Cell and Nanomedicine, Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Shanghai 200120, China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Wang
authors.affiliation: SARI Center for Stem Cell and Nanomedicine, Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Shanghai 200120, China.
authors.forename: Jenny
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Peking University Stem Cell Research Center, China National Center for International Research, Peking University Health Science Center, Beijing 100191, China; SARI Center for Stem Cell and Nanomedicine, Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Shanghai 200120, China. Electronic address: lils@sari.ac.cn.
authors.forename: Lingsong
authors.initials: L
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055786:Gene Knockout Techniques; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D051796:Inhibitor of Differentiation Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C490903:Tob1 protein, mouse; C485732:Tob2 protein, mouse; C067679:Idb3 protein, mouse
keywords: Anti-proliferation; Double knockout ESCs; Embryonic stem cells; Tob subfamily