Abstract
The levels, regulation and prognostic value of p21 in head and neck squamous cell carcinomas (HNSCC) has been puzzling for years. Here, we report a new mechanism of regulation of p21 by the mTORC1/4E-BP1 pathway. We find that non-phosphorylated 4E-BP1 interacts with p21 and induces its degradation. Accordingly, hyper-activation of mTORC1 results in phosphorylation of 4E-BP1 and stabilization of p21. In HNSCC, p21 levels strongly correlate with mTORC1 activity but not with p53 status. Finally, clinical data indicate that HNSCC patients with p21 and phospho-S6-double-positive tumours present a better disease-specific survival. We conclude that over-activation of the mTORC1/4E-BP1/p21 pathway is a frequent and clinically relevant alteration in HNSCC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adult
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Aged
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Aged, 80 and over
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism*
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Cell Cycle Proteins
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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Female
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease
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Head and Neck Neoplasms / genetics
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Head and Neck Neoplasms / metabolism*
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Humans
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Male
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Mechanistic Target of Rapamycin Complex 1
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Middle Aged
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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EIF4EBP1 protein, human
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Multiprotein Complexes
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Phosphoproteins
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases