Abstract
Mutations in the SMN1 (survival motor neuron 1) gene cause spinal muscular atrophy (SMA). We now show that SMN protein, the SMN1 gene product, interacts directly with the tumor suppressor protein, p53. Pathogenic missense mutations in SMN reduce both self-association and p53 binding by SMN, and the extent of the reductions correlate with disease severity. The inactive, truncated form of SMN produced by the SMN2 gene in SMA patients fails to bind p53 efficiently. SMN and p53 co-localize in nuclear Cajal bodies, but p53 redistributes to the nucleolus in fibroblasts from SMA patients. These results suggest a functional interaction between SMN and p53, and the potential for apoptosis when this interaction is impaired may explain motor neuron death in SMA.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Apoptosis
-
Biosensing Techniques
-
Cell Line
-
Cyclic AMP Response Element-Binding Protein
-
Dimerization
-
Exons
-
Fibroblasts / metabolism
-
Glutathione Transferase / metabolism
-
Humans
-
Immunohistochemistry
-
Microscopy, Fluorescence
-
Muscular Atrophy, Spinal / genetics*
-
Muscular Atrophy, Spinal / metabolism*
-
Mutation
-
Mutation, Missense
-
Nerve Tissue Proteins / genetics*
-
Nerve Tissue Proteins / metabolism*
-
Precipitin Tests
-
Protein Binding
-
Protein Structure, Tertiary
-
RNA-Binding Proteins
-
Recombinant Proteins / metabolism
-
SMN Complex Proteins
-
Survival of Motor Neuron 1 Protein
-
Survival of Motor Neuron 2 Protein
-
Time Factors
-
Transfection
-
Tumor Cells, Cultured
-
Tumor Suppressor Protein p53 / metabolism*
-
Tumor Suppressor Protein p53 / physiology*
Substances
-
Cyclic AMP Response Element-Binding Protein
-
Nerve Tissue Proteins
-
RNA-Binding Proteins
-
Recombinant Proteins
-
SMN Complex Proteins
-
SMN1 protein, human
-
SMN2 protein, human
-
Survival of Motor Neuron 1 Protein
-
Survival of Motor Neuron 2 Protein
-
Tumor Suppressor Protein p53
-
Glutathione Transferase