GAMT, a p53-inducible modulator of apoptosis, is critical for the adaptive response to nutrient stress.
The p53 tumor suppressor protein has a well-established role in cell-fate decision-making processes. However, recent discoveries indicate that p53 has a non-tumor-suppressive role. Here we identify guanidinoacetate methyltransferase (GAMT), an enzyme involved in creatine synthesis, as a p53 target gene and a key downstream effector of adaptive response to nutrient stress. We show that GAMT is not only involved in p53-dependent apoptosis in response to genotoxic stress but is important for apoptosis induced by glucose deprivation. Additionally, p53-->GAMT upregulates fatty acid oxidation (FAO) induced by glucose starvation, utilizing this pathway as an alternate ATP-generating energy source. These results highlight that p53-dependent regulation of GAMT allows cells to maintain energy levels sufficient to undergo apoptosis or survival under conditions of nutrient stress. The p53-->GAMT pathway represents a new link between cellular stress responses and processes of creatine synthesis and FAO, demonstrating a further role of p53 in cellular metabolism.
Ide
Takao
T
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Brown-Endres
Lauren
L
Chu
Kiki
K
Ongusaha
Pat P
PP
Ohtsuka
Takao
T
El-Deiry
Wafik S
WS
Aaronson
Stuart A
SA
Lee
Sam W
SW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003401:Creatine / Q000096:biosynthesis; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005720:Gamma Rays; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D050937:Guanidinoacetate N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D005227:Fatty Acids; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D000255:Adenosine Triphosphate; C494507:Gamt protein, mouse; D050937:Guanidinoacetate N-Methyltransferase; D005947:Glucose; D003401:Creatine