mTOR signaling in growth control and disease.

doi:10.1016/J.CELL.2012.03.017

Home
/
Papers
/
mTOR signaling in growth control and disease.

Journal Article•DOI•

mTOR signaling in growth control and disease.

Mathieu Laplante¹, David M. Sabatini¹•Institutions (1)

Massachusetts Institute of Technology¹

13 Apr 2012-Cell (CELL)-Vol. 149, Iss: 2, pp 274-293

TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.

read less

About: This article is published in Cell.The article was published on 2012-04-13 and is currently open access. It has received 5792 citations till now. The article focuses on the topics: RPTOR & PI3K/AKT/mTOR pathway.

...read moreread less

Citations

PDF

Open Access

More filters

Journal Article•DOI•

The Hallmarks of Aging

[...]

Carlos López-Otín¹, Maria A. Blasco, Linda Partridge², Manuel Serrano, Guido Kroemer² - Show less +1 more•Institutions (2)

University of Oviedo¹, Max Planck Society²

06 Jun 2013-Cell

TL;DR: Nine tentative hallmarks that represent common denominators of aging in different organisms are enumerated, with special emphasis on mammalian aging, to identify pharmaceutical targets to improve human health during aging, with minimal side effects.

...read moreread less

9,980 citations

Cites background from "mTOR signaling in growth control an..."

...Altered Intercellular Communication Beyond cell-autonomous alterations, aging also involves changes at the level of intercellular communication, be it endocrine, neuroendocrine, or neuronal (Laplante and Sabatini, 2012; Rando and Chang, 2012; Russell and Kahn, 2007; Zhang et al., 2013) (Figure 5C)....
[...]
...The mTOR kinase is part of two multiprotein complexes, mTORC1 and mTORC2, that regulate essentially all aspects of anabolic metabolism (Laplante and Sabatini, 2012)....
[...]

Journal Article•DOI•

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

[...]

Chih-Hao Chang¹, Jing Qiu¹, David O’Sullivan¹, Michael D. Buck¹, Takuro Noguchi¹, Jonathan D. Curtis¹, Qiongyu Chen¹, Mariel Gindin¹, Matthew M. Gubin¹, Gerritje J.W. van der Windt¹, Elena Tonc¹, Robert D. Schreiber¹, Edward J. Pearce¹, Erika L. Pearce¹ - Show less +10 more•Institutions (1)

Washington University in St. Louis¹

10 Sep 2015-Cell

TL;DR: It is shown that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer, and it is found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of gly colysis enzymes.

...read moreread less

1,983 citations

Cites background from "mTOR signaling in growth control an..."

...Given that mTOR directly regulates mRNA translation and ribosome biogenesis (Laplante and Sabatini, 2012), we analyzed protein expression of several glycolysis enzymes after PD-L1 blockade....
[...]
...To further explore glucose competition, we impaired R tumor glycolysis with an inhibitor of mechanistic target of rapamycin (mTOR) (Kim et al., 2002; Laplante and Sabatini, 2012), or promoted glycolysis with the Akt activator 4-hydroxytamoxifen (4-HT) (Doughty et al., 2006; Kohn et al., 1998)…...
[...]
...To further explore glucose competition, we impaired R tumor glycolysis with an inhibitor of mechanistic target of rapamycin (mTOR) (Kim et al., 2002; Laplante and Sabatini, 2012), or promoted glycolysis with the Akt activator 4-hydroxytamoxifen (4-HT) (Doughty et al....
[...]

Journal Article•DOI•

Fundamentals of cancer metabolism

[...]

Ralph J. DeBerardinis¹, Navdeep S. Chandel²•Institutions (2)

University of Texas Southwestern Medical Center¹, Northwestern University²

01 May 2016-Science Advances

TL;DR: A conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis will progressively support the development of new strategies to treat human cancer.

...read moreread less

Abstract: Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

...read moreread less

1,850 citations

Cites background from "mTOR signaling in growth control an..."

...mTORC1 is stimulated by the presence of amino acids and activates protein synthesis via its effects on translation and ribosome biogenesis (80)....
[...]
...This kinase is inhibited when amino acids and oxygen levels are diminished (80)....
[...]

Journal Article•DOI•

PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase.

[...]

Gommaar D'Hulst¹, Inés Soro-Arnaiz¹, Evi Masschelein¹, Koen Veys², Gillian Fitzgerald¹, Benoit Smeuninx³, Sunghoon Kim⁴, Louise Deldicque⁵, Bert Blaauw⁶, Peter Carmeliet², Leigh Breen³, Peppi Koivunen⁷, Shimin Zhao⁸, Shimin Zhao⁹, Katrien De Bock¹ - Show less +11 more•Institutions (9)

École Polytechnique Fédérale de Lausanne¹, Katholieke Universiteit Leuven², University of Birmingham³, Seoul National University⁴, Université catholique de Louvain⁵, University of Padua⁶, University of Oulu⁷, Sichuan University⁸, Fudan University⁹

10 Jan 2020-Nature Communications

TL;DR: The authors show that the PHD1 controls muscle mass in a hydroxylation-independent manner and prevents the degradation of leucine sensor LRS during oxygen and amino acid depletion to ensure effective mTORC1 activation in response to leucines.

...read moreread less

Abstract: mTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. We show that loss of the prolyl hydroxylase domain isoform 1 oxygen sensor in mice (PHD1KO) reduces muscle mass. PHD1KO muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Mechanistically, PHD1 interacts with and stabilizes LRS. This interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation. Finally, elderly subjects have lower PHD1 levels and LRS activity in muscle from aged versus young human subjects. In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity.

...read moreread less

1,466 citations

Journal Article•DOI•

PI3K and cancer: lessons, challenges and opportunities

[...]

David A. Fruman¹, Christian Rommel²•Institutions (2)

University of California, Irvine¹, Amgen²

01 Feb 2014-Nature Reviews Drug Discovery

TL;DR: Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

...read moreread less

Abstract: The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

...read moreread less

1,396 citations

1
2
3
4
…
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200

Collapse

References

PDF

Open Access

More filters

Journal Article•DOI•

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

[...]

Vamsi K. Mootha¹, Cecilia M. Lindgren², Cecilia M. Lindgren¹, Karl-Fredrik Eriksson², Aravind Subramanian¹, Smita Sihag¹, J. Lehar¹, Pere Puigserver³, Emma Carlsson², Martin Ridderstråle², Esa Laurila², Nicholas E. Houstis¹, Mark J. Daly¹, Nick Patterson¹, Jill P. Mesirov¹, Todd R. Golub³, Todd R. Golub¹, Pablo Tamayo¹, Bruce M. Spiegelman³, Eric S. Lander¹, Joel N. Hirschhorn¹, Joel N. Hirschhorn³, Joel N. Hirschhorn⁴, David Altshuler, Leif Groop² - Show less +21 more•Institutions (4)

Massachusetts Institute of Technology¹, Lund University², Harvard University³, Boston Children's Hospital⁴

01 Jul 2003-Nature Genetics

TL;DR: An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.

...read moreread less

Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

...read moreread less

7,997 citations

Patent•DOI•

Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

[...]

David M. Sabatini¹, Dos D. Sarbassov¹•Institutions (1)

Massachusetts Institute of Technology¹

27 Jan 2006-Science

TL;DR: In this paper, the rictor-mTOR complex was used to identify compounds which modulate Akt activity mediated by the Rictor mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activation.

...read moreread less

Abstract: In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.

...read moreread less

5,430 citations

Journal Article•DOI•

Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

[...]

Taichi Hara¹, Kenji Nakamura², Makoto Matsui¹, Makoto Matsui³, Makoto Matsui⁴, Akitsugu Yamamoto⁵, Yohko Nakahara², Rika Suzuki-Migishima², Minesuke Yokoyama⁶, Kenji Mishima⁷, Ichiro Saito⁷, Hideyuki Okano⁸, Noboru Mizushima¹ - Show less +9 more•Institutions (8)

Institute of Medical Science¹, Mitsubishi², Graduate University for Advanced Studies³, National Institute for Basic Biology, Japan⁴, Nagahama Institute of Bio-Science and Technology⁵, Niigata University⁶, Tsurumi University⁷, Keio University⁸

15 Jun 2006-Nature

TL;DR: The results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

...read moreread less

Abstract: Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

...read moreread less

3,684 citations

"mTOR signaling in growth control an..." refers background in this paper

...Additionally, deletion of the essential autophagy gene Atg5 or Atg7 in the central nervous system of mice promotes the accumulation of polyubiquitinated proteins and neurodegeneration, even in the absence of any disease-associated mutant proteins (Hara et al., 2006; Komatsu et al., 2006)....
[...]

Journal Article•DOI•

TSC2 mediates cellular energy response to control cell growth and survival.

[...]

Ken Inoki¹, Tianqing Zhu¹, Kun-Liang Guan¹•Institutions (1)

University of Michigan¹

26 Nov 2003-Cell

TL;DR: It is described that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis.

...read moreread less

3,647 citations

"mTOR signaling in growth control an..." refers background in this paper

...Adenosine monophosphate-activated protein kinase (AMPK), in response to hypoxia or a low energy state, phosphorylates TSC2 and increases its GAP activity toward Rheb (Inoki et al., 2003b)....
[...]
...The GTP-bound form of Rheb directly interacts with mTORC1 and strongly stimulates its kinase activity....
[...]
...A current model posits that at the lysosomal surface mTORC1 can bind to and become activated by Rheb, which is found throughout the endomembrane system....
[...]
...Given that so many signals regulate mTORC1 through TSC1/2, it is surprising that we still do not know how TSC1/2 integrates, at the molecular level, the inputs to control its GAP activity toward Rheb....
[...]
...To date, there is no credible evidence that a guanine nucleotide exchange factor (GEF) exists for Rheb....
[...]

Journal Article•DOI•

Loss of autophagy in the central nervous system causes neurodegeneration in mice

[...]

Masaaki Komatsu¹, Satoshi Waguri², Satoshi Waguri³, Tomoki Chiba¹, Shigeo Murata¹, Junichi Iwata¹, Junichi Iwata⁴, Isei Tanida⁴, Takashi Ueno⁴, Masato Koike², Yasuo Uchiyama², Eiki Kominami⁴, Keiji Tanaka¹ - Show less +9 more•Institutions (4)

Institute of Medical Science¹, Osaka University², Fukushima Medical University³, Juntendo University⁴

15 Jun 2006-Nature

TL;DR: It is found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.

...read moreread less

Abstract: Protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells. In addition to the ubiquitin-proteasome system, emerging evidence points to the importance of autophagy--the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover--in the protein quality-control process. However, little is known about the precise roles of autophagy in neurons. Here we report that loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. We found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.

...read moreread less

3,349 citations

"mTOR signaling in growth control an..." refers background in this paper

...Additionally, deletion of the essential autophagy gene Atg5 or Atg7 in the central nervous system of mice promotes the accumulation of polyubiquitinated proteins and neurodegeneration, even in the absence of any disease-associated mutant proteins (Hara et al., 2006; Komatsu et al., 2006)....
[...]