Abstract
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.
Highlights
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF506968
Alternative names conferred on the NF90 family include human mitotic phase phosphoprotein 4 (MPP4) [6], Xenopus 4F.1 and 4F.2 [7], murine interleukin enhancer binding factor (ILF)-3 [8], translation control protein (TCP)-80 [9], double-stranded RNA-binding protein (DRBP)-76 [10], and nuclear factor associated with RNA (NFAR)-1 and 2 [11]
The dsRBMs of CCAATbox transcription factor (CBTF) are capable of binding both DNA and RNA [21], and intact dsRBMs are required for transcriptional control [15]
Summary
Vol 280, No 19, Issue of May 13, pp. 18981–18989, 2005 Printed in U.S.A. Differentiation by Direct Binding to the 3-Untranslated Region of MyoD and p21WAF1/CIP1 mRNAs*. 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. NF90 binds to AU-rich elements in the 3Ј-UTR of IL-2 mRNA, stabilizing IL-2 mRNA against rapid degradation, and contributing to the up-regulation of IL-2 gene expression in activated T-cells [23]. Muscle development is regulated through the coordinated expression of myogenic regulatory factors that include MyoD, Myf, myogenin, and Mrf, and cyclin-dependent kinase inhibitors of the p21WAF1/CIP1 family [34, 35]. In differentiating myoblasts and regenerating adult muscle, up-regulation of MyoD, myogenin, and p21WAF1/CIP1 expression occurs concurrently through transcriptional mechanisms and post-transcriptional mRNA stabilization by specific RNA-binding proteins [35, 36]. Our results led us to propose that the phenotype of muscle weakness and increased apoptosis in NF90(Ϫ/Ϫ) mice is explained by defects in skeletal myocyte differentiation arising from insufficient expression of myogenic regulatory factors
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