Research on Progress and Prospect of Kinase S6K1_Journal of Biomedical Engineering

Authors：

 ZHANGHui ^1,2 , LIANGJunyu ¹ , ZHANGJi ¹

1. College of Life Science, Northwest Normal University, Lanzhou 730070, China;
2. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

ZHANGHui, Email: zhanghui123gansu@163.com

Keywords：

kinase S6K1; obesity; molecular mechanisms; inhibitor

DOI：

10.7507/1001-5515.20140176

Video：

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Obesity is a prevalent metabolic disorder,which seriously affects human health and has become the world's public health problem. Kinase S6K1, an important downstream effector of mammalian target of rapamycin (mTOR), influences specific pathological responses, including obesity, type 2 diabetes and cancer. Presently, S6K1 has become an attractive therapeutic target in the treatment of these disorders. Here, the functions of kinase S6K1, its molecular regulation mechanisms, related pathogenesis of disease and relevant small molecular inhibitors are reviewed. Finally, the prospect of research toward S6K1 is expected as well.

Citation： ZHANGHui, LIANGJunyu, ZHANGJi. Research on Progress and Prospect of Kinase S6K1. Journal of Biomedical Engineering, 2014, 31(4): 935-938,949. doi: 10.7507/1001-5515.20140176 Copy

1.	ZHANG A, SUN H, WANG X. Power of metabolomics in biomarker discovery and mining mechanisms of obesity[J]. Obes Rev, 2013,14(4):344-349.
2.	杨永青, 杨明庆. 肥胖诱发胰岛素抵抗的炎性机制[J]. 中国生物化学与分子生物学报,2012,28(8): 692-699.
3.	YUAN H X, XIONG Y, GUAN K L. Nutrient sensing, metabolism, and cell growth control[J]. Mol Cell,2013, 49(3): 379-387.
4.	UM S H, FRIGERIO F, WATANABE M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity[J]. Nature, 2004, 431(7007): 200-205.
5.	FENTONA T R, GOUTB I T. Functions and regulation of the 70 kDa ribosomal S6 kinases[J]. Int J Biochem Cell Biol, 2011,43(1): 47-59.
6.	SUNAMI T, BYRNE N, DIEHL R E, et al. Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation[J]. J Biol Chem, 2010, 285(7): 4587-4594.
7.	UM S H, D'ALESSIO D , THOMAS G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1[J]. Cell Metab, 2006, 3(6): 393-402.
8.	MAGNUSON B, EKIM B, FINGAR D C. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks[J]. Biochem J, 2012, 441(1): 1-21.
9.	CORNU M, ALBERT V, HALL M N. mTOR in aging, metabolism, and cancer[J]. Curr Opin Genet Dev, 2013, 23(1):53-62.
10.	MANNING B D. Insulin signaling: inositol phosphates get into the akt[J]. Cell, 2010, 143(6): 861-863.
11.	EFEYAN A, SABATI D M. mTOR and cancer: many loops in one pathway[J]. Curr Opin Cell Biol, 2010, 22(2):169-176.
12.	HAMILTON D L, PHILP A, MACKENZIE M G, et al. Prolonged activation of S6K1 does not suppress IRS or PI-3 kinase signaling during muscle cell differentiation[J]. BMC Cell Biol, 2010, 11: 37.
13.	ROBERTO Z, LIRON B P, ALEJO E. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase[J]. Science, 2011, 334(6056): 678-683.
14.	QUY P N, KUMA A, PIERRE P, et al. Poteasome-dependent activation of mammalian target of rapamycin complex 1(mTORC1) is essential for autophagy suppression and muscle remodeling following denervation[J]. J Biol Chem, 2013, 288(2): 1125-1134.
15.	SELMAN C, TULLET J M , WIESER D, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span[J]. Scences, 2009, 326(5949): 140-144.
16.	OLDHAM S. Obesity and nutrient sensing TOR pathway in flies and vertebrates: Functional conservation of genetic mechanisms[J]. Trends Endocrinol Metab, 2011, 22(2): 45-52.
17.	MANDAVIA C H, PULAKAT L, DEMARCO V, et al. Over-nutrition and metabolic cardiomyopathy[J]. Metabolism, 2012, 61(9):1205-1210.
18.	张颖,郝进. mTORComplex1/S6K1信号通路在2型糖尿病发生发展中的作用[J]. 重庆医学, 2012, 31(41):3333-3335.
19.	刘效磊,牛燕媚,傅力. mTOR/S6K1信号通路研究进展[J]. 中国运动医学杂志, 2010, 29(1):118-121.
20.	PULAKAT L, DEMARCO V G, ARDHANARI S, et al. Adaptive mechanisms to compensate for overnutrition-induced cardiovascular abnormalities[J]. Am J Physiol Regul Integr Comp Physiol, 2011, 301(4):R885-R895.
21.	SOWERS J R, WHALEY-CONNELL A, HAYDEN M R. The role of overweight and obesity in the cardiorenal syndrome[J]. Cardiorenal Med, 2011, 1(1): 5-12.
22.	BOSE S K, SHRIVASTAVA S, MEYER K, et al. Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance[J]. J Virol, 2012, 86(11):6315-6322.
23.	VEILLEUX A, HOUDE V P, BELLMANN K, et al. Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes[J]. Mol Endocrinol, 2010, 24(4):766-778.
24.	MORENO-NAVARRETE J M, ORTEGA F, SÁNCHEZ-GARRIDOB M, et al. Phosphorylated S6K1(Thr389) is a molecular adipose tissue marker of altered glucose tolerance[J]. J Nutr Biochem, 2013, 24(1): 32-38.
25.	BEDFORD D C. S6K1: reducing the Risks of aging[J]. Dis Model Mech, 2010, 3(3-4): 123-124.
26.	BEN-HUR V, DENICHENKO P, SIEGFRIED Z, et al. S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1[J]. Cell Reports, 2013,3(1):103-115.
27.	PÉREZ-TENORIO G, KARLSSON E, WALTERSSON M A, et al. Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer[J]. Breast Cancer Res Treat, 2011, 128(3): 713-723.
28.	HOLZ M K. The role of S6K1 in ER-positive breast cancer[J]. Cell Cycle, 2012, 11(17): 3159-3165.
29.	MARUANI D M, SPIEGE T N, HARRIS E N, et al. Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation[J]. Oncogene, 2012, 31(49): 5073-5080.
30.	ISMAIL H M. Overexpression of s6 kinase 1 in brain tumours is associated with induction of hypoxia-responsive genes and predicts patients' survival[J]. J Oncol, 2012.
31.	BANDARAGE U, HARE B, PARSONS J, et al. 4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors[J]. Bioorg Med Chem Lett, 2009, 19(17): 5191-5194.
32.	YE P, KUHN C, JUAN M, et al. Potent and selective thiophene urea-templated inhibitors of S6K[J]. Bioorg Med Chem Lett, 2011, 21(2): 849-852.
33.	BUSSENIUS J, ANAND N K, BLAZEY C M, et al. Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(6): 2283-2286.
34.	LEE W H, KIM Y W, CHOI J H, et al. Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1α activity through p70 ribosomal S6 kinase-1 inhibition and H₂O₂-scavenging effect[J]. Mol Cancer Ther, 2009, 8(10): 2791-2802.

1. ZHANG A, SUN H, WANG X. Power of metabolomics in biomarker discovery and mining mechanisms of obesity[J]. Obes Rev, 2013,14(4):344-349.
2. 杨永青, 杨明庆. 肥胖诱发胰岛素抵抗的炎性机制[J]. 中国生物化学与分子生物学报,2012,28(8): 692-699.
3. YUAN H X, XIONG Y, GUAN K L. Nutrient sensing, metabolism, and cell growth control[J]. Mol Cell,2013, 49(3): 379-387.
4. UM S H, FRIGERIO F, WATANABE M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity[J]. Nature, 2004, 431(7007): 200-205.
5. FENTONA T R, GOUTB I T. Functions and regulation of the 70 kDa ribosomal S6 kinases[J]. Int J Biochem Cell Biol, 2011,43(1): 47-59.
6. SUNAMI T, BYRNE N, DIEHL R E, et al. Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation[J]. J Biol Chem, 2010, 285(7): 4587-4594.
7. UM S H, D'ALESSIO D , THOMAS G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1[J]. Cell Metab, 2006, 3(6): 393-402.
8. MAGNUSON B, EKIM B, FINGAR D C. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks[J]. Biochem J, 2012, 441(1): 1-21.
9. CORNU M, ALBERT V, HALL M N. mTOR in aging, metabolism, and cancer[J]. Curr Opin Genet Dev, 2013, 23(1):53-62.
10. MANNING B D. Insulin signaling: inositol phosphates get into the akt[J]. Cell, 2010, 143(6): 861-863.
11. EFEYAN A, SABATI D M. mTOR and cancer: many loops in one pathway[J]. Curr Opin Cell Biol, 2010, 22(2):169-176.
12. HAMILTON D L, PHILP A, MACKENZIE M G, et al. Prolonged activation of S6K1 does not suppress IRS or PI-3 kinase signaling during muscle cell differentiation[J]. BMC Cell Biol, 2010, 11: 37.
13. ROBERTO Z, LIRON B P, ALEJO E. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase[J]. Science, 2011, 334(6056): 678-683.
14. QUY P N, KUMA A, PIERRE P, et al. Poteasome-dependent activation of mammalian target of rapamycin complex 1(mTORC1) is essential for autophagy suppression and muscle remodeling following denervation[J]. J Biol Chem, 2013, 288(2): 1125-1134.
15. SELMAN C, TULLET J M , WIESER D, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span[J]. Scences, 2009, 326(5949): 140-144.
16. OLDHAM S. Obesity and nutrient sensing TOR pathway in flies and vertebrates: Functional conservation of genetic mechanisms[J]. Trends Endocrinol Metab, 2011, 22(2): 45-52.
17. MANDAVIA C H, PULAKAT L, DEMARCO V, et al. Over-nutrition and metabolic cardiomyopathy[J]. Metabolism, 2012, 61(9):1205-1210.
18. 张颖,郝进. mTORComplex1/S6K1信号通路在2型糖尿病发生发展中的作用[J]. 重庆医学, 2012, 31(41):3333-3335.
19. 刘效磊,牛燕媚,傅力. mTOR/S6K1信号通路研究进展[J]. 中国运动医学杂志, 2010, 29(1):118-121.
20. PULAKAT L, DEMARCO V G, ARDHANARI S, et al. Adaptive mechanisms to compensate for overnutrition-induced cardiovascular abnormalities[J]. Am J Physiol Regul Integr Comp Physiol, 2011, 301(4):R885-R895.
21. SOWERS J R, WHALEY-CONNELL A, HAYDEN M R. The role of overweight and obesity in the cardiorenal syndrome[J]. Cardiorenal Med, 2011, 1(1): 5-12.
22. BOSE S K, SHRIVASTAVA S, MEYER K, et al. Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance[J]. J Virol, 2012, 86(11):6315-6322.
23. VEILLEUX A, HOUDE V P, BELLMANN K, et al. Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes[J]. Mol Endocrinol, 2010, 24(4):766-778.
24. MORENO-NAVARRETE J M, ORTEGA F, SÁNCHEZ-GARRIDOB M, et al. Phosphorylated S6K1(Thr389) is a molecular adipose tissue marker of altered glucose tolerance[J]. J Nutr Biochem, 2013, 24(1): 32-38.
25. BEDFORD D C. S6K1: reducing the Risks of aging[J]. Dis Model Mech, 2010, 3(3-4): 123-124.
26. BEN-HUR V, DENICHENKO P, SIEGFRIED Z, et al. S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1[J]. Cell Reports, 2013,3(1):103-115.
27. PÉREZ-TENORIO G, KARLSSON E, WALTERSSON M A, et al. Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer[J]. Breast Cancer Res Treat, 2011, 128(3): 713-723.
28. HOLZ M K. The role of S6K1 in ER-positive breast cancer[J]. Cell Cycle, 2012, 11(17): 3159-3165.
29. MARUANI D M, SPIEGE T N, HARRIS E N, et al. Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation[J]. Oncogene, 2012, 31(49): 5073-5080.
30. ISMAIL H M. Overexpression of s6 kinase 1 in brain tumours is associated with induction of hypoxia-responsive genes and predicts patients' survival[J]. J Oncol, 2012.
31. BANDARAGE U, HARE B, PARSONS J, et al. 4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors[J]. Bioorg Med Chem Lett, 2009, 19(17): 5191-5194.
32. YE P, KUHN C, JUAN M, et al. Potent and selective thiophene urea-templated inhibitors of S6K[J]. Bioorg Med Chem Lett, 2011, 21(2): 849-852.
33. BUSSENIUS J, ANAND N K, BLAZEY C M, et al. Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(6): 2283-2286.
34. LEE W H, KIM Y W, CHOI J H, et al. Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1α activity through p70 ribosomal S6 kinase-1 inhibition and H₂O₂-scavenging effect[J]. Mol Cancer Ther, 2009, 8(10): 2791-2802.

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