DNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here, we find that DNA damage triggers a critical block in glutamine metabolism, which is required ...for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression.
► DNA damage induces SIRT4 and inhibits mitochondrial glutamine metabolism ► SIRT4 is required for proper repression of glutamine metabolism after DNA damage ► SIRT4 loss promotes genomic instability ► SIRT4 represses tumor growth, and SIRT4 knockout mice develop tumors with age
Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap ...with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.
Display omitted
•Hepatic H2S production capacity is elevated in long-lived hypopituitary mouse models•Growth hormone (GH) represses hepatic H2S production post-transcriptionally•Thyroid hormone (TH) acts via TRβ to repress cystathionine γ-lyase and H2S levels•H2S negatively regulates circulating TH and IGF-1 levels
Reduced thyroid hormone (TH) and growth hormone (GH) activity are hallmarks of genetic models of longevity in mice. Here, Hine et al. find that TH and GH negatively regulate hepatic production of the longevity-associated gas hydrogen sulfide, which feeds back to negatively regulate circulating TH and IGF-1 levels.
The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung carcinoma, LKB1 is somatically inactivated ...in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to define novel therapeutic targets in KRAS-driven LKB1-mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling showed that Lkb1-null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1-wild-type cells. Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors.
XBP1 is a critical transcriptional activator of the unfolded protein response (UPR), which increases tumor cell survival under prolonged endoplasmic reticulum (ER) stress and hypoxic conditions.This ...study was designed to evaluate the immunogenicity of heteroclitic XBP1 unspliced (US)
184-192
(YISPWILAV) and heteroclictic XBP1 spliced (SP)
367-375
(YLFPQLISV) HLA-A2 peptides, and to characterize the specific activities of XBP1 peptides-specific cytotoxic T lymphocytes (XBP1-CTL) against breast cancer, colon cancer, and pancreatic cancer cells.The XBP1-CTL had upregulated expression of critical T cell markers and displayed HLA-A2-restricted and antigen-specific activities against breast cancer, colon cancer and pancreatic cancer cells. XBP1-CTL were enriched withCD45RO
+
memory CTL, which showed high expression of critical T cell markers (CD28, ICOS, CD69, CD40L), cell proliferation and antitumor activities as compared to CD45RO
−
non-memory CTL. The effector memory (EM: CD45RO
+
CCR7
−
) subset had the highest level of cell proliferation while the central memory (CM: CD45RO
+
CCR7
+
) subset demonstrated enhanced functional activities (CD107a degranulation, IFNγ/IL-2 production) upon recognition of the respective tumor cells. Furthermore, both the EM and CM XBP1-CTL subsets expressed high levels of Th1 transcription regulators Tbet and Eomes. The highest frequencies of IFNγ or granzyme B producing cells were detected within CM XBP1-CTL subset that were either Tbet
+
or Eomes
+
in responding to the tumor cells.These results demonstrate the immunotherapeutic potential of a cocktail of immunogenic HLA-A2 specific heteroclitic XBP1 US
184-192
and heteroclictic XBP1 SP
367-375
peptides to induce CD3
+
CD8
+
CTL enriched for CM and EM cells with specific antitumor activities against a variety of solid tumors.
Familial neurogenic tumor syndromes Kimmelman, A; Liang, B C
Hematology/oncology clinics of North America,
12/2001, Letnik:
15, Številka:
6
Journal Article
Recenzirano
Cancer caused more than 0.5 million deaths in the United States in 2000. This estimate includes patients who have a genetic predisposition to neoplastic disease, including brain neoplasms. Familial ...tumor syndromes are important to identify clinically because family members require high degrees of monitoring and genetic counseling. Study of these individuals and families has led to the discovery of genes that are an intrinsic aspect of cell regulation and will continue to be relevant in defining mechanisms of neoplastic development in brain and other tissues.
PDF
