Differential Expression of S6K2 Dictates Tissue-Specific Requirement for S6K1 in Mediating Aberrant mTORC1 Signaling and Tumorigenesis

The S6K1 and S6K2 kinases are considered important mTOR signaling effectors, yet their contribution to tumorigenesis remains unclear. Aberrant mTOR activation is a frequent event in cancer that commonly results from heterozygous loss of PTEN. Here, we show for the first time a differential protein e...

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Published inCancer research (Chicago, Ill.) Vol. 71; no. 10; pp. 3669 - 3675
Main Authors NARDELLA, Caterina, LUNARDI, Andrea, FEDELE, Giuseppe, CLOHESSY, John G, ALIMONTI, Andrea, KOZMA, Sara C, THOMAS, George, LODA, Massimo, PAOLO PANDOLFI, Pier
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 15.05.2011
Subjects
Animals
Antineoplastic agents
Biological and medical sciences
Cell Line, Tumor
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Heterozygote
Humans
Mechanistic Target of Rapamycin Complex 1
Medical sciences
Mice
Mice, Transgenic
Multiprotein Complexes
Pharmacology. Drug treatments
Pheochromocytoma - genetics
Proteins - metabolism
Ribosomal Protein S6 Kinases, 70-kDa - biosynthesis
TOR Serine-Threonine Kinases
Tumors
Tissue specificity
Signal transduction
Tumorigenicity
Gene expression
Carcinogenesis
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Summary:The S6K1 and S6K2 kinases are considered important mTOR signaling effectors, yet their contribution to tumorigenesis remains unclear. Aberrant mTOR activation is a frequent event in cancer that commonly results from heterozygous loss of PTEN. Here, we show for the first time a differential protein expression between S6K1 and S6K2 in both mouse and human tissues. Additionally, the inactivation of S6k1 in the context of Pten heterozygosity (Pten(+/-)) suggests a differential requirement for this protein across multiple tissues. This tissue specificity appears to be governed by the relative protein expression of S6k2. Accordingly, we find that deletion of S6k1 markedly impairs Pten(+/-) mediated adrenal tumorigenesis, specifically due to low expression of S6k2. Concomitant observation of low S6K2 levels in the human adrenal gland supports the development of S6K1 inhibitors for treatment of PTEN loss-driven pheochromocytoma.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-10-3962