NF90 regulates cell cycle exit and terminal myogenic differentiation by direct binding to the 3'-untranslated region of MyoD and p21WAF1/CIP1 mRNAs.
NF90 and splice variant NF110/ILF3/NFAR are double-stranded RNA-binding proteins that regulate gene expression. Mice with targeted disruption of NF90 were engineered. NF90(-/-) mice were born small and weak and succumbed to perinatal death within 12 h because of neuromuscular respiratory failure. Lung inflation and morphology were normal in NF90(-/-) mice. The diaphragm and other skeletal muscles in NF90(-/-) mice demonstrated disorganized arrangement and paucity of myofibers, evidence of myocyte degeneration and increased apoptosis. The expression of myogenic regulators, MyoD, myogenin, and p21WAF1/CIP1, was severely decreased in NF90(-/-) mice. These myogenic transcription factors and cell cycle inhibitors are regulated in part through post-transcriptional mRNA stabilization. Northwestern blotting revealed that NF90 is the principal and specific p21WAF1/CIP1 and MyoD 3'-untranslated region RNA-binding protein in developing skeletal muscles. NF90 regulates transcription factors and a cell cycle inhibitor essential for skeletal muscle differentiation and for survival.
Shi
Lingfang
L
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Zhao
Guohua
G
Qiu
Daoming
D
Godfrey
Wayne R
WR
Vogel
Hannes
H
Rando
Thomas A
TA
Hu
Hong
H
Kao
Peter N
PN
D020413:3' Untranslated Regions; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D002454:Cell Differentiation; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D005838:Genotype; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D008168:Lung / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D017570:MyoD Protein / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009474:Neurons / Q000378:metabolism; D050779:Nuclear Factor 90 Proteins; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D009690:Nucleic Acid Conformation; D010641:Phenotype; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D020413:3' Untranslated Regions; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C494015:Ilf3 protein, mouse; D017570:MyoD Protein; D050778:NFATC Transcription Factors; D050779:Nuclear Factor 90 Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors