Oncogenesis

Cyclin D1

Zhonghua Kou Qiang Yi Xue Za Zhi. 2006 Jul;41(7):407-10. Links

[Expression of tumor suppressor gene PTEN, PIP3 and cyclin D1 in oral squamous cell carcinoma and their correlations]

[Article in Chinese]

· Xie SM, Shen LJ, Yin C, Ruan P, Yao X.

Graduate College, Southern Medical University, Guangzhou 510515, China.

OBJECTIVE: To detect the expression of PTEN, PIP3 and cyclin D1 in oral squamous cell carcinoma and precancerous lesions and analyze their correlation. METHODS: Immunohistochemistry SP method was used to detect the expression of PTEN, PIP3 and cyclin D1 in 63 cases of oral squamous cell carcinoma, 29 cases of simple hyperplasia, 33 cases of dysplasia, and 25 cases of normal oral mucosa. RESULTS: The negative or low expression of PTEN in oral squamous cell carcinoma was 25%, which was remarkably lower than that in other groups. The positive expression of PIP3 in simple hyperplasia, dysplasia and oral squamous cell carcinoma was 66%, 64%, and 76% respectively, which were much higher than those in normal oral mucosa. The positive expression of cyclin D1 in oral squamous cell carcinoma was 49%, which was significantly higher than that in other groups. The negative correlation between PTEN with PIP3, cyclin D1 and the positive correlation between PIP3 and cyclin D1 were observed. CONCLUSIONS: PTEN may play a role in the oncogenesis of oral squamous cell carcinoma, and PTEN may down-regulate the expression of PIP3, and then down-regulate the expression of cyclin D1, which leads to the suppression of cell growth.

PMID: 17067457 [PubMed - in process]

J Clin Invest. 2006 Jul;116(7):1886-901. Epub 2006 Jun 22. Links

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity.

· Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Munzberg H, Shanabrough M, Burdakov D, Rother E, Janoschek R, Alber J, Belgardt BF, Koch L, Seibler J, Schwenk F, Fekete C, Suzuki A, Mak TW, Krone W, Horvath TL, Ashcroft FM, Bruning JC.

Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne (CMMC), Cologne, Germany.

Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.

PMID: 16794735 [PubMed - indexed for MEDLINE]

BMC Biol. 2006 Feb 3;4:1. Links

Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm.

· Weinkove D, Halstead JR, Gems D, Divecha N.

Department of Biology, University College London, London WC1E 6BT, UK. d.weinkove@ucl.ac.uk

BACKGROUND: The provision of stress resistance diverts resources from development and reproduction and must therefore be tightly regulated. In Caenorhabditis elegans, the switch to increased stress resistance to promote survival through periods of starvation is regulated by the DAF-16/FOXO transcription factor. Reduction-of-function mutations in AGE-1, the C. elegans Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a daf-16 dependent manner. Class IA PI3Ks downregulate FOXOs by inducing their translocation to the cytoplasm. However, the circumstances under which AGE-1 is normally activated are unclear. To address this question we used C. elegans first stage larvae (L1s), which when starved enter a developmentally-arrested diapause stage until food is encountered. RESULTS: We find that in L1s both starvation and daf-16 are necessary to confer resistance to oxidative stress in the form of hydrogen peroxide. Accordingly, DAF-16 is localised to cell nuclei after short-term starvation. However, after long-term starvation, DAF-16 unexpectedly translocates to the cytoplasm. This translocation requires functional age-1. H2O2 treatment can replicate the translocation and induce generation of the AGE-1 product PIP3. Because feeding reduces to zero in ageing adult C. elegans, these animals may also undergo long-term starvation. Consistent with our observation in L1s, DAF-16 also translocates to the cytoplasm in old adult worms in an age-1-dependent manner. CONCLUSION: DAF-16 is activated in the starved L1 diapause. The translocation of DAF-16 to the cytoplasm after long-term starvation may be a feedback mechanism that prevents excessive expenditure on stress resistance. H2O2 is a candidate second messenger in this feedback mechanism. The lack of this response in age-1(hx546) mutants suggests a novel mechanism by which this mutation increases longevity.

PMID: 16457721 [PubMed - indexed for MEDLINE]