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Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis.
Oncogene. 2010 Dec 16; 29(50):6543-56.O

Abstract

Tuberous sclerosis complex (TSC) is an autosomally inherited disorder that causes tumors to form in many organs. It is frequently caused by inactivating mutations in the TSC2 tumor-suppressor gene. TSC2 negatively regulates the activity of the GTPase Rheb and thereby inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling. Activation of mTORC1 as a result of lack of TSC2 function is observed in TSC and sporadic lymphangioleiomyomatosis (LAM). TSC2 deficiency has recently been associated with elevated AMP-activated protein kinase (AMPK) activity, which in turn correlated with cytoplasmic localization of p27Kip1 (p27), a negative regulator of cyclin-dependent kinase 2 (Cdk2). How AMPK in the absence of TSC2 is stimulated is not fully understood. In this study, we demonstrate that Rheb activates AMPK and reduces p27 levels in Tsc2-null cells. Importantly, both effects occur largely independent of mTORC1. Furthermore, increased p27 levels following Rheb depletion correlated with reduced Cdk2 activity and cell proliferation in vitro, and with inhibition of tumor formation by Tsc2-null cells in vivo. Taken together, our data suggest that Rheb controls proliferation of TSC2-deficient cells by a mechanism that involves regulation of AMPK and p27, and that Rheb is a potential target for TSC/LAM therapy.

Authors+Show Affiliations

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

20818424

Citation

Lacher, M D., et al. "Rheb Activates AMPK and Reduces p27Kip1 Levels in Tsc2-null Cells Via mTORC1-independent Mechanisms: Implications for Cell Proliferation and Tumorigenesis." Oncogene, vol. 29, no. 50, 2010, pp. 6543-56.
Lacher MD, Pincheira R, Zhu Z, et al. Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis. Oncogene. 2010;29(50):6543-56.
Lacher, M. D., Pincheira, R., Zhu, Z., Camoretti-Mercado, B., Matli, M., Warren, R. S., & Castro, A. F. (2010). Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis. Oncogene, 29(50), 6543-56. https://doi.org/10.1038/onc.2010.393
Lacher MD, et al. Rheb Activates AMPK and Reduces p27Kip1 Levels in Tsc2-null Cells Via mTORC1-independent Mechanisms: Implications for Cell Proliferation and Tumorigenesis. Oncogene. 2010 Dec 16;29(50):6543-56. PubMed PMID: 20818424.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis. AU - Lacher,M D, AU - Pincheira,R, AU - Zhu,Z, AU - Camoretti-Mercado,B, AU - Matli,M, AU - Warren,R S, AU - Castro,A F, Y1 - 2010/09/06/ PY - 2010/9/7/entrez PY - 2010/9/8/pubmed PY - 2011/1/12/medline SP - 6543 EP - 56 JF - Oncogene JO - Oncogene VL - 29 IS - 50 N2 - Tuberous sclerosis complex (TSC) is an autosomally inherited disorder that causes tumors to form in many organs. It is frequently caused by inactivating mutations in the TSC2 tumor-suppressor gene. TSC2 negatively regulates the activity of the GTPase Rheb and thereby inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling. Activation of mTORC1 as a result of lack of TSC2 function is observed in TSC and sporadic lymphangioleiomyomatosis (LAM). TSC2 deficiency has recently been associated with elevated AMP-activated protein kinase (AMPK) activity, which in turn correlated with cytoplasmic localization of p27Kip1 (p27), a negative regulator of cyclin-dependent kinase 2 (Cdk2). How AMPK in the absence of TSC2 is stimulated is not fully understood. In this study, we demonstrate that Rheb activates AMPK and reduces p27 levels in Tsc2-null cells. Importantly, both effects occur largely independent of mTORC1. Furthermore, increased p27 levels following Rheb depletion correlated with reduced Cdk2 activity and cell proliferation in vitro, and with inhibition of tumor formation by Tsc2-null cells in vivo. Taken together, our data suggest that Rheb controls proliferation of TSC2-deficient cells by a mechanism that involves regulation of AMPK and p27, and that Rheb is a potential target for TSC/LAM therapy. SN - 1476-5594 UR - https://www.unboundmedicine.com/medline/citation/20818424/Rheb_activates_AMPK_and_reduces_p27Kip1_levels_in_Tsc2_null_cells_via_mTORC1_independent_mechanisms:_implications_for_cell_proliferation_and_tumorigenesis_ L2 - https://doi.org/10.1038/onc.2010.393 DB - PRIME DP - Unbound Medicine ER -