Cobalt and nickel stabilize stem cell transcription factor OCT4 through modulating its sumoylation and ubiquitination.
Stem cell research can lead to the development of treatments for a wide range of ailments including diabetes, heart disease, aging, neurodegenerative diseases, spinal cord injury, and cancer. OCT4 is a master regulator of self-renewal of undifferentiated embryonic stem cells. OCT4 also plays a crucial role in reprogramming of somatic cells into induced pluripotent stem (iPS) cells. Given known vivo reproductive toxicity of cobalt and nickel metals, we examined the effect of these metals on expression of several stem cell factors in embryonic Tera-1 cells, as well as stem cells. Cobalt and nickel induced a concentration-dependent increase of OCT4 and HIF-1α, but not NANOG or KLF4. OCT4 induced by cobalt and nickel was due primarily to protein stabilization because MG132 stabilized OCT4 in cells treated with either metals and because neither nickel nor cobalt significantly modulated its steady-state mRNA level. OCT4 stabilization by cobalt and nickel was mediated largely through reactive oxygen species (ROS) as co-treatment with ascorbic acid abolished OCT4 increase. Moreover, nickel and cobalt treatment increased sumoylation and mono-ubiquitination of OCT4 and K123 was crucial for mediating these modifications. Combined, our observations suggest that nickel and cobalt may exert their reproductive toxicity through perturbing OCT4 activity in the stem cell compartment.
Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York, United States of America.
Yixin
Y
Yao
Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York, United States of America.
Yinghua
Y
Lu
Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York, United States of America.
Wen-Chi
WC
Chen
Biopharmaceutical Research Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.
Yongping
Y
Jiang
Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Tao
T
Cheng
Yupo Ma, Department of Pathology, The State University of New York at Stony Brook, Stony Brook, New York, United States of America.
Yupo
Y
Ma
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, California, United States of America.
Lou
L
Lu
Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York, United States of America ; Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, Tuxedo, New York, United States of America.
Wei
W
Dai
D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009532:Nickel / Q000494:pharmacology*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D050814:Octamer Transcription Factor-3; D003035:Cobalt; D009532:Nickel; D008239:Lysine