Thalidomide induces limb anomalies by PTEN stabilization, Akt suppression, and stimulation of caspase-dependent cell death.

Molecular and Cellular Biology
Jürgen KnoblochUlrich Rüther

Abstract

Thalidomide, a drug used for the treatment of multiple myeloma and inflammatory diseases, is also a teratogen that causes birth defects, such as limb truncations and microphthalmia, in humans. Thalidomide-induced limb truncations result from increased cell death during embryonic limb development and consequential disturbance of limb outgrowth. Here we demonstrate in primary human embryonic cells and in the chicken embryo that thalidomide-induced signaling through bone morphogenetic proteins (Bmps) protects active PTEN from proteasomal degradation, resulting in suppression of Akt signaling. As a consequence, caspase-dependent cell death is stimulated by the intrinsic and Fas death receptor apoptotic pathway. Most importantly, thalidomide-induced limb deformities and microphthalmia in chicken embryos could be rescued by a pharmacological PTEN inhibitor as well as by insulin, a stimulant of Akt signaling. We therefore conclude that perturbation of PTEN/Akt signaling and stimulation of caspase activity is central to the teratogenic effects of thalidomide.

References

Oct 1, 1992·Journal of Medical Genetics·R W Smithells, C G Newman
Nov 15, 1965·Experientia·P B SawinH M Wuest
Jan 1, 1995·Developmental Dynamics : an Official Publication of the American Association of Anatomists·C N Dealy, R A Kosher
Feb 12, 1998·The Journal of Biological Chemistry·M AndjelkovićB A Hemmings
Apr 8, 1998·Current Opinion in Genetics & Development·D R Alessi, P Cohen
Dec 2, 1999·Genes & Development·S R DattaM E Greenberg
Jul 27, 2000·The Journal of Biological Chemistry·V W DingF McCormick
Mar 30, 2001·The Journal of Biological Chemistry·S FukumotoM E Lee
May 22, 2001·Molecular and Cellular Biology·L SimpsonR Parsons
Jun 1, 2002·Circulation Research·Stefan E Hardt, Junichi Sadoshima
Mar 26, 2003·Cell Death and Differentiation·M E Peter, P H Krammer
Sep 21, 1963·Nature·C A DEBOCK, A PETERS
Jan 28, 2004·Cell·Nika N Danial, Stanley J Korsmeyer
Apr 7, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Henning R GockelNorbert Lügering
May 19, 2004·FEBS Letters·Annette C SchmidRüdiger Woscholski
Jun 15, 2004·The Biochemical Journal·Nick R Leslie, C Peter Downes
Oct 12, 2004·Experimental Cell Research·Juliet M TaylorRocco C Iannello
Oct 27, 2005·Journal of Biochemistry and Molecular Biology·Dohoon Kim, Jongkyeong Chung
Nov 2, 2005·Journal of Bone and Mineral Metabolism·Kazuhito SugimoriIsao Kitajima
Feb 24, 2006·Nature Reviews. Molecular Cell Biology·Cullen M TaniguchiC Ronald Kahn
Jun 24, 2006·The Journal of Biological Chemistry·Michael D Gordon, Roel Nusse
Sep 22, 2006·Antioxidants & Redox Signaling·Nick R Leslie
Sep 30, 2006·Cell Death and Differentiation·D ChauvierE Jacotot
Dec 28, 2006·Apoptosis : an International Journal on Programmed Cell Death·Soo-Jeong LimJung Sik Cho
Jan 16, 2007·Cell·Xinjiang WangXuejun Jiang
Feb 7, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jürgen KnoblochUlrich Rüther

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Citations

Jan 8, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Peter G WellsAndrea W Wong
Jan 6, 2011·Cellular and Molecular Life Sciences : CMLS·Takumi ItoHiroshi Handa
May 13, 2009·Molecular Pharmaceutics·Jürgen KnoblochUlrich Rüther
Jun 6, 2015·Birth Defects Research. Part C, Embryo Today : Reviews·Neil Vargesson
Jul 3, 2015·Molecular Medicine Reports·Zhiqi FangXiaoyu Chen
Nov 19, 2009·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Neil Vargesson
Dec 22, 2009·Birth Defects Research. Part B, Developmental and Reproductive Toxicology·Jan L Reichard-BrownKatherine McBride
Dec 11, 2017·Progress in Neuro-psychopharmacology & Biological Psychiatry·Muhammad Imran KhanAhmad Reza Dehpour
Feb 21, 2021·British Journal of Clinical Pharmacology·Lakshmikirupa SundaresanSuvro Chatterjee
Sep 19, 2018·Nature Chemical Biology·Peter G Wells
Apr 30, 2019·Birth Defects Research·Shama BhatiaPeter G Wells
Aug 20, 2016·Frontiers in Physiology·Benjamin KalbeSabrina Osterloh
Oct 28, 2016·Birth Defects Research. Part C, Embryo Today : Reviews·Peter G AlexanderRocky S Tuan
Aug 17, 2010·American Journal of Respiratory and Critical Care Medicine·Jürgen KnoblochAndrea Koch
Nov 17, 2010·Leukemia & Lymphoma·Javier de la Rubia, Esperanza Such
Apr 20, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Crystal J J LeePeter G Wells
Apr 21, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Crystal J J LeePeter G Wells
Apr 22, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·James H Kim, Anthony R Scialli
Feb 22, 2012·Congenital Anomalies·Takumi Ito, Hiroshi Handa
Apr 3, 2012·Drug Discoveries & Therapeutics·H Maruta
Aug 3, 2013·Evolutionary Bioinformatics Online·Yongzhong Zhao, Richard J Epstein
Dec 19, 2013·Congenital Anomalies·Yoshinori KawamuraKeiichiro Sato
Jan 1, 2014·Acta Biochimica Et Biophysica Sinica·Xiubao ChangA Keith Stewart
Aug 1, 2009·Birth Defects Research. Part A, Clinical and Molecular Teratology·Trent D Stephens
Feb 11, 2010·Developmental Biology·Oliver LievenUlrich Rüther
Jun 12, 2010·Current Opinion in Genetics & Development·Rolf Zeller

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