TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

doi:10.1016/J.CELL.2006.05.036

Home
/
Papers
/
TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

Journal Article•DOI•

TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

Karim Bensaad, Atsushi Tsuruta, Mary A. Selak, M. Nieves Calvo Vidal¹, Katsunori Nakano, Ramon Bartrons¹, Eyal Gottlieb, Karen H. Vousden - Show less +4 more•Institutions (1)

University of Barcelona¹

14 Jul 2006-Cell (Cell Press)-Vol. 126, Iss: 1, pp 107-120

TL;DR: expression of TIGAR may modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired, and the decrease of intracellular ROS levels in response to TIGar may also play a role in the ability of p53 to protect from the accumulation of genomic damage.

read less

About: This article is published in Cell.The article was published on 2006-07-14 and is currently open access. It has received 1803 citations till now. The article focuses on the topics: TP53-inducible glycolysis and apoptosis regulator & Apoptosis Regulator.

...read moreread less

Citations

PDF

Open Access

More filters

Journal Article•DOI•

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

[...]

Matthew G. Vander Heiden¹, Lewis C. Cantley¹, Craig B. Thompson²•Institutions (2)

Harvard University¹, University of Pennsylvania²

22 May 2009-Science

TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.

...read moreread less

Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

...read moreread less

12,380 citations

Journal Article•DOI•

ROS Function in Redox Signaling and Oxidative Stress

[...]

Michael Schieber¹, Navdeep S. Chandel¹•Institutions (1)

Northwestern University¹

19 May 2014-Current Biology

TL;DR: It is argued that redox biology, rather than oxidative stress, underlies physiological and pathological conditions.

...read moreread less

4,297 citations

Cites background from "TIGAR, a p53-Inducible Regulator of..."

...TIGAR functions as a fructose-2,6-bisphosphatase, lowering the levels of fructose-2,6-bisphosphate, a positive regulator of phosphofructokinase-1 [57]....
[...]

Journal Article•DOI•

Regulation of cancer cell metabolism

[...]

Rob A. Cairns, Isaac S. Harris, Tak W. Mak

01 Feb 2011-Nature Reviews Cancer

TL;DR: Interest in the topic of tumour metabolism has waxed and waned over the past century, but it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

...read moreread less

Abstract: Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

...read moreread less

4,169 citations

Cites background from "TIGAR, a p53-Inducible Regulator of..."

...However, p53 inhibits the glycolytic pathway by upregulating the expression of TP53-induced glycolysis and apoptosis regulator (TIGAR), an enzyme that decreases the levels of the glycolytic activator fructose-2,6-bisphosphat...
[...]

Journal Article•DOI•

Blinded by the Light: The Growing Complexity of p53

[...]

Karen H. Vousden, Carol Prives¹•Institutions (1)

Columbia University¹

01 May 2009-Cell

TL;DR: Control of p53's transcriptional activity is crucial for determining which p53 response is activated, a decision that must be understood if the next generation of drugs that selectively activate or inhibit p53 are to be exploited efficiently.

...read moreread less

2,775 citations

Cites background from "TIGAR, a p53-Inducible Regulator of..."

..., 2008), dampening glycolysis (Bensaad et al., 2006; Kondoh et al., 2005), and enhancing mitochondrial respiration (Ma et al....
[...]
...These recently uncovered functions include modulating glucose uptake (Kawauchi et al., 2008), dampening glycolysis (Bensaad et al., 2006; Kondoh et al., 2005), and enhancing mitochondrial respiration (Ma et al., 2007)....
[...]
...Although this function for p53 would help inhibit tumor progression by protecting cells against DNA damage and genome instability, downregulation of reactive oxygen species through these p53dependent mechanisms can also result in decreased susceptibility to apoptosis (Bensaad et al., 2006)....
[...]
...dependent mechanisms can also result in decreased susceptibility to apoptosis (Bensaad et al., 2006)....
[...]

Journal Article•DOI•

Modulation of oxidative stress as an anticancer strategy.

[...]

Chiara Gorrini¹, Isaac S. Harris², Isaac S. Harris¹, Tak W. Mak¹•Institutions (2)

University Health Network¹, Harvard University²

01 Dec 2013-Nature Reviews Drug Discovery

TL;DR: The controversial role of ROS in tumour development and in responses to anticancer therapies is addressed, and the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact is elaborate.

...read moreread less

Abstract: The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.

...read moreread less

2,639 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•

On the origin of cancer cells.

[...]

Otto Warburg¹•Institutions (1)

Max Planck Society¹

24 Feb 1956-Science

10,654 citations

Origin of cancer cells

[...]

Otto Warburg

01 Jan 1956

8,572 citations

"TIGAR, a p53-Inducible Regulator of..." refers background in this paper

...Finally, one of the hallmark of cancer cells is an increased glycolytic rate (Warburg, 1956), which is frequently accompanied by elevated levels of Fru-2,6-P2 (Chesney et al....
[...]
...Finally, one of the hallmark of cancer cells is an increased glycolytic rate (Warburg, 1956), which is frequently accompanied by elevated levels of Fru-2,6-P2 (Chesney et al., 1999; Nissler et al., (F) Flow cytometric analysis of U2OS cells transfected with expression plasmids for Flag-tagged TIGAR…...
[...]

Journal Article•DOI•

Surfing the p53 network

[...]

Bert Vogelstein¹, David P. Lane², Arnold J. Levine³•Institutions (3)

Howard Hughes Medical Institute¹, University of Dundee², Rockefeller University³

16 Nov 2000-Nature

TL;DR: The p53 tumour-suppressor gene integrates numerous signals that control cell life and death, and the disruption of p53 has severe consequences when a highly connected node in the Internet breaks down.

...read moreread less

Abstract: The p53 tumour-suppressor gene integrates numerous signals that control cell life and death. As when a highly connected node in the Internet breaks down, the disruption of p53 has severe consequences.

...read moreread less

6,605 citations

"TIGAR, a p53-Inducible Regulator of..." refers background in this paper

...…p53 has been shown to be involved in the induction of apoptosis, cell-cycle arrest, senescence, and differentiation—responses that prevent further proliferation of stressed or damaged cells and so protect from the outgrowth of cells harboring malignant alterations (Vogelstein et al., 2000)....
[...]
...Stress-induced activation of p53 leads to the induction of expression of a large number of p53 target genes, several of which have been shown to play an important role in mediating the various responses to p53 (Vogelstein et al., 2000)....
[...]
...p53 has been shown to be involved in the induction of apoptosis, cell-cycle arrest, senescence, and differentiation—responses that prevent further proliferation of stressed or damaged cells and so protect from the outgrowth of cells harboring malignant alterations (Vogelstein et al., 2000)....
[...]

Journal Article•DOI•

In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.

[...]

Lyubomir T. Vassilev¹, Binh Thanh Vu¹, Bradford Graves¹, Daisy Carvajal¹, Frank John Podlaski¹, Zoran Filipovic¹, Norman Kong¹, Ursula Kammlott¹, Christine Lukacs¹, Christian Klein¹, Nader Fotouhi¹, Liu Emily Aijun¹ - Show less +8 more•Institutions (1)

Hoffmann-La Roche¹

06 Feb 2004-Science

TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.

...read moreread less

Abstract: MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.

...read moreread less

4,397 citations

"TIGAR, a p53-Inducible Regulator of..." refers background in this paper

...To further assess the ability of TIGAR to modulate p53-induced apoptosis, we examined the effect of treatment of the cells with Nutlin-3, a direct and specific activator of p53 (Vassilev et al., 2004)....
[...]

Journal Article•DOI•

Live or let die: the cell's response to p53

[...]

Karen H. Vousden¹, Xin Lu²•Institutions (2)

National Institutes of Health¹, Ludwig Institute for Cancer Research²

01 Aug 2002-Nature Reviews Cancer

TL;DR: Understanding the complex mechanisms that regulate whether or not a cell dies in response to p53 will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

...read moreread less

Abstract: Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

...read moreread less

3,242 citations

"TIGAR, a p53-Inducible Regulator of..." refers background in this paper

...The p53 tumor-suppressor protein plays a critical role in responding to cellular stress and inhibiting malignant development (Vousden and Lu, 2002)....
[...]