Antagonists of BMP and TGF beta signalling pathway

A transforming growth factor, active technology, applied to the nucleic acid, oligonucleotide or nucleic acid encoding the Smurf protein of the present invention, the antibody that specifically binds to the Smurf protein, and the human Smurf protein field, which can solve the problems of elusive mechanism and purpose.

Inactive Publication Date: 2008-04-09
THE RES FOUND OF STATE UNIV OF NEW YORK +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Mechanisms and purpose of ubiquitination in con

Method used

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  • Antagonists of BMP and TGF beta signalling pathway
  • Antagonists of BMP and TGF beta signalling pathway
  • Antagonists of BMP and TGF beta signalling pathway

Examples

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Embodiment 1

[0216] Smurf1 targets the BMP pathway and affects embryonic patterning The TGFβ superfamily regulates various biological processes, including cell growth, differentiation, and patterning. Any dysregulation of TGFβ signaling may cause disease. The signal to activate the TGFβ receptor is directly transduced from the receptor to the nucleus by the Smad protein. Several links between ubiquitin-mediated degradation and the regulation of morphogenetic signals during development are now established. This example illustrates a novel E3 ubiquitin ligase, Smurf1, that selectively interacts with BMP pathway-specific Smads, leading to their ubiquitination, degradation and inactivation. In amphibian embryos, Smurf1 specifically blocks BMP signaling to affect patterning. Thus, ubiquitination against Smads may function to control embryonic development and various cellular responses to TGFβ signaling.

[0217] method

[0218] Yeast two-hybrid screening Xenopus Smad1 cDNA (36) was cloned...

Embodiment 2

[0254] Example 2: Characterization and cloning of human Smurf2

[0255] Human Smurf2 was identified and cloned using the Xenopus Smurf1 sequence from the EST database. Two overlapping EST clones corresponding to hSmurf2 were obtained and used to construct the full-length sequence of hSmurf2. Smurf2 is closely related to Smurf1, and its amino acid sequence homology with hSmurf1 is about 75%. Smurf2 contains an amino-terminal C2 domain followed by three WW domains and a HECT ubiquitin ligase domain ( Figure 12 ). Smurf2 is closely related to Smurf1, but has an additional WW domain downstream of the C2 domain ( Figure 13 ). Smurf2 was found to be expressed throughout early development and to be present in most adult tissues, with lower levels in the spleen and skeletal muscle ( Figure 14 A and Figure 14 B). RT-PCR analysis further showed that Smurf2 was expressed in various cell lines including P19, HepG2 and 293T.

[0256] Isolation of human Smurf2 and mouse Smurf2...

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Abstract

This invention provides unique members of the Hect family of ubiquitin ligases that specifically target BMP and TGF beta /activin pathway-specific Smads. The novel ligases have been named Smurf1 and Smurf2. They directly interact with Smads1 and 5 and Smad7, respectively, and regulate the ubiquitination, turnover and activity of Smads and other proteins of these pathways. Smurf1 interferes with biological responses to BMP, but not activin signalling. In amphibian embryos Smurf1 inhibits endogenous BMP signals, resulting in altered pattern formation and cell fate specification in the mesoderm and ectoderm. The present invention provides a unique regulatory link between the ubiquitination pathway and the control of cell fate determination by the TGF beta superfamily during embryonic development. Thus, Smurf1 is a negative regulator of Smad1 signal transduction, by targeting Smad1, Smurf1 blocks BMP signalling. In mammalian cells, Smurf2 suppresses TGF beta signalling, and in Xenopus, blocks formation of dorsal mesoderm and causes anterior truncation of the embryos. Smurf2 forms a stable complex with Smad7, which induces degradation and downregulation of TGF beta /activin signalling.

Description

[0001] Research leading to this invention was supported in part by the National Institutes of Health under grant number SR01HD3242902. Accordingly, the US Government has certain rights in this invention. Background of the invention [0002] In virtually all animal phyla, key steps in embryonic development are regulated by cell-to-cell signaling or induced signals mediated by secreted growth factors. Specifically, members of the transforming growth factor beta (TGFβ) superfamily regulate a variety of cellular and developmental processes such as mitosis, cell differentiation, embryonic patterning, and organogenesis. In vertebrate embryos, various TGFβ signals affect germ layer specification, body patterning, cell growth and differentiation (1-4). In the amphibian Xenopus embryos, different TGFβ members induce different cell fates, eg activin, Vgl and nodal induce embryonic dorsal mesoderm features such as notochord and muscle. Vgl and activins also induce endoderm characterist...

Claims

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Application Information

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IPC IPC(8): C07H21/04C12N15/00C07K14/00A01K67/027A61K31/7088A61K38/00A61K39/395A61K45/00A61K48/00A61P19/08A61P25/00A61P27/02A61P43/00C07K16/40C12N1/15C12N1/19C12N1/21C12N5/10C12N9/00C12N15/09C12Q1/02G01N33/15G01N33/50G01N33/53
CPCC12N9/93A01K2217/05A61P19/08A61P25/00A61P27/02A61P43/00
Inventor G·H·汤姆森J·弗拉纳
Owner THE RES FOUND OF STATE UNIV OF NEW YORK
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