A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles

Pollizzi, Kristen; Malinowska-Kolodziej, Izabela; Doughty, Cheryl A.; Betz, Charles; Ma, Jian; Goto, June; Kwiatkowski, David J.

doi:10.1093/hmg/ddp176

Cited by 29 publications

(40 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate whether mTOR regulation of PKM2 exists in tumor samples, we checked mouse kidney tumors driven by up-regulated mTOR in a TSC mouse model (Tsc2 del3/+ ) (30). As expected, these kidney tumor samples exhibited robust elevation of Pkm2 (Fig.…”

Section: Resultsmentioning

confidence: 57%

Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth

Sun

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

506

441

View full text Add to dashboard Cite

Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/ AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism. We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1α (HIF1α)-mediated transcription activation, and c-Myc-heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells. Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1α/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway.PTEN | tuberous sclerosis 1 | hexokinase II | lactate dehydrogenase-B | glyceraldehyde 3-phosphate dehydrogenase U nlike in normal cells, glycolysis is induced by hypoxia, and cancer cells preferentially metabolize glucose by glycolysis, even in an aerobic environment (1-3). Increased glucose consumption and an elevated rate of lactate production by cancer cells are characteristics of glycolysis, first described by Otto Warburg in the 1920s and thereafter known as the Warburg effect (4). Because this altered metabolism can occur even in the presence of oxygen, glycolysis presumably confers a selective advantage for the survival and proliferation of cancer cells. This catabolic process is, however, inefficient for energy production in that it generates only 2 mol of ATP, instead of an additional 36 mol through the tricarboxylic acid (TCA) cycle, in the presence of oxygen by using 1 mol of glucose (2, 3, 5).Although the Warburg effect is a well-recognized hallmark of cancer metabolism, its regulatory mechanism is still largely obscure. Critical issues, including how and when cancer cells acquire this highly glycolytic phenoty...

show abstract

Section: Resultsmentioning

confidence: 57%

Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth

Sun

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

506

441

View full text Add to dashboard Cite

show abstract

“…For Figure 2B, the kidney tumors were from 2 heterozygous Tsc2 exon 3 deletion (Tsc2 del3/+ ) mice (19 and 22 months old), and the kidneys were from 2 WT mice (22 and 23 months old) (35). For Figure 7D, the tumors from Tsc2 +/-mice and kidneys from WT mice were previously described (31).…”

Section: Adipocyte Differentiation Mef Cells Were Transduced With Pmmentioning

confidence: 99%

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Ma¹,

Meng²,

Kwiatkowski³

et al. 2010

J. Clin. Invest.

Self Cite

214

217

View full text Add to dashboard Cite

The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.

show abstract

“…Recently, MEF cell lines have also been isolated from mice expressing a hypomorphic Tsc2 allele (Tsc2 del3=del3 ), and these also display activated mTORC1 signaling. 91 In addition to MEF cell lines, a line of neuroepithelial progenitor (NEP) has also been established from Tsc2-null mice. 92 These cells exhibit an aberrant differentiation pattern resembling giant cells of human tumors and express b-III tubulin and GFAP.…”

Section: Cells Derived From Knockout Micementioning

confidence: 99%

Lymphangioleiomyomatosis andTSC2^-/-Cells

Darling

Pacheco–Rodriguez

Gorio

et al. 2010

Lymphatic Research and Biology

View full text Add to dashboard Cite

The cells comprising pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipomas (AMLs) are heterogeneous, with variable mixtures of cells exhibiting differentiation towards smooth muscle, fat, and vessels. Cells grown from LAM and AMLs have likewise tended to be heterogeneous. The discovery that LAM and AMLs contain cells with mutations in the TSC1 or TSC2 genes is allowing investigators to discriminate between ''two-hit'' cells and neighboring cells, providing insights into disease pathogenesis. In rare cases, it has been possible to derive cells from human tumors, including AMLs and TSC skin tumors that are highly enriched for TSC2 -=-cells. Cells derived from an Eker rat uterine leiomyoma (ELT3 cells) are Tsc2-null and these have been used in a rodent cell models for LAM. Further improvements in the ability to reliably grow well-characterized TSC2 -=-cells from human tumors are critical to developing in vitro and in vivo model systems for studies of LAM pathogenesis and treatment.

show abstract

A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles

Cited by 29 publications

References 35 publications

Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth

Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Lymphangioleiomyomatosis andTSC2^-/-Cells

Contact Info

Product

Resources

About

A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles

Cited by 29 publications

References 35 publications

Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth

Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Lymphangioleiomyomatosis andTSC2-/-Cells

Contact Info

Product

Resources

About

Lymphangioleiomyomatosis andTSC2^-/-Cells