title: Differential expression of S6K2 dictates tissue-specific requirement for S6K1 in mediating aberrant mTORC1 signaling and tumorigenesis.
abstract: 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.
authors: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Caterina
authors: C
authors: Nardella
authors: Andrea
authors: A
authors: Lunardi
authors: Giuseppe
authors: G
authors: Fedele
authors: John G
authors: JG
authors: Clohessy
authors: Andrea
authors: A
authors: Alimonti
authors: Sara C
authors: SC
authors: Kozma
authors: George
authors: G
authors: Thomas
authors: Massimo
authors: M
authors: Loda
authors: Pier Paolo
authors: PP
authors: Pandolfi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D010673:Pheochromocytoma / Q000235:genetics; D011506:Proteins / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis*; D058570:TOR Serine-Threonine Kinases
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2