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1.  Interplay between the Westerlies and Asian monsoon recorded in Lake Qinghai sediments since 32 ka 
Scientific Reports  2012;2:619.
Two atmospheric circulation systems, the mid-latitude Westerlies and the Asian summer monsoon (ASM), play key roles in northern-hemisphere climatic changes. However, the variability of the Westerlies in Asia and their relationship to the ASM remain unclear. Here, we present the longest and highest-resolution drill core from Lake Qinghai on the northeastern Tibetan Plateau (TP), which uniquely records the variability of both the Westerlies and the ASM since 32 ka, reflecting the interplay of these two systems. These records document the anti-phase relationship of the Westerlies and the ASM for both glacial-interglacial and glacial millennial timescales. During the last glaciation, the influence of the Westerlies dominated; prominent dust-rich intervals, correlated with Heinrich events, reflect intensified Westerlies linked to northern high-latitude climate. During the Holocene, the dominant ASM circulation, punctuated by weak events, indicates linkages of the ASM to orbital forcing, North Atlantic abrupt events, and perhaps solar activity changes.
doi:10.1038/srep00619
PMCID: PMC3431539  PMID: 22943005
2.  Down-Regulation of Inhibitor of Apoptosis Proteins by Deguelin Selectively Induces Apoptosis in Breast Cancer Cells 
Molecular pharmacology  2006;71(1):101-111.
The identification of differentially regulated apoptotic signals in normal and tumor cells allows the development of cancer cell-selective therapies. Increasing evidence shows that the inhibitor of apoptosis (IAP) proteins survivin and XIAP are highly expressed in tumor cells but are absent or have very low levels of expression in normal adult tissues. We found that inhibiting AKT activity with 10 to 100 nM deguelin, a small molecule derived from natural products, markedly reduced the levels of both survivin and XIAP, inducing apoptosis in human breast cancer cells but not in normal cells. It is noteworthy that we detected an elevated level of cleaved poly(ADP-ribose) polymerase, a signature of caspase activation, without a significant increase in caspase activity in deguelin-treated cancer cells. Our results suggest that severe down-regulation of the IAPs by deguelin releases their inhibitory activity over pre-existing active caspases present in cancer cells, inducing apoptosis without the need for further caspase activation. Because normal cells have very low levels of p-AKT, XIAP, survivin, and preexisting caspase activity, deguelin had little effect on those cells. In addition, we found that combining deguelin with chemotherapy drugs enhanced drug-induced apoptosis selectively in human tumor cells, which suggests that deguelin has great potential for chemosensitization and could represent a new therapeutic agent for treatment of breast cancer.
doi:10.1124/mol.106.027367
PMCID: PMC3132577  PMID: 17035597
3.  LKB1 is Necessary for Akt-mediated Phosphorylation of Pro-apoptotic Proteins 
Cancer research  2008;68(18):7270-7277.
LKB1 plays the role of tumor suppressor, opposite to Akt, by negatively regulating mTOR through the activation of AMPK and TSC signaling. We have discovered a novel, potentially oncogenic role for LKB1, as a supporter of Akt-mediated phosphorylation of pro-apoptotic proteins. We found that Akt activation led to increased phosphorylation of FoxO3a at threonine 32 (Thr32) in LKB1 wild-type cells, but not in LKB1-null cells. Depletion of LKB1 in the cells with wild-type LKB1 resulted in attenuation of that phosphorylation of FoxO3a by activated Akt, while the restoration of LKB1 function in LKB1-null cells re-established Akt-mediated FoxO3a phosphorylation. Upon expanding our analysis to other Akt targets, using isogenic LKB1 knockdown cell line pairs and a phospho-specific antibody microarray, we observed that there was a requirement for LKB1 in the phosphorylation of other Akt down-stream targets, including Ask1 (Ser83), Bad (Ser136), FoxO1 (Ser319), FoxO4 (Ser197) and GSK3β (Ser9). Because the phosphorylation of these sites by Akt suppresses apoptosis, the requirement of LKB1 suggests that LKB1 may have an anti-apoptotic role in tumor cells with constitutively active Akt. Indeed, we found the suppression of LKB1 expression led to apoptosis in three cell lines in which Akt is constitutively active, but not in two cell lines without Akt activation. This observation may explain the lack of LKB1 somatic mutations in brain, breast and colon cancers, where Akt is frequently activated due to mutations in PI3K, PTEN or Akt itself.
doi:10.1158/0008-5472.CAN-08-1484
PMCID: PMC2596073  PMID: 18794113
LKB1; PI3K/Akt signaling; tumor suppressor; apoptosis
4.  Sox7 is an independent checkpoint for β-catenin function in prostate and colon epithelial cells 
Molecular cancer research : MCR  2008;6(9):1421-1430.
The presence of somatic β-catenin mutations in some prostate cancers implies that aberrant WNT signaling is involved in the cancer’s development. Although β-catenin stability is regulated by a multi-component destruction complex, mutational alterations of β-catenin or other components of the destruction complexes are rare in prostate tumors. Therefore, β-catenin may be regulated by another protein in the prostate. In fact, recent linkage and somatic deletion analyses in prostate cancers reveal a 1.4 Mb candidate tumor suppressor locus on 8p23.1, which includes the Sox7 gene. Here we show that Sox7 protein expression was indeed down-regulated in 47% (15/32) of prostate adenocarcinomas. Also, Sox7 mRNA was down-regulated in 60% of snap-frozen tumors. This down-regulation was found to be due to tumor-specific promoter hypermethylation, which was present in 48% (10/21) of primary prostate tumors and 44% (11/25) of prostate cancer cell lines/xenografts. We discovered that Sox7 protein physically interacts with β-catenin and suppresses β-catenin-mediated transcription by depleting active β-catenin. Furthermore, in HCT116 colorectal cancer cell lines with Sox7 inactivation, ectopic Sox7 expression suppressed cell proliferation and inhibited transcription that was activated by an endogenous mutant β-catenin. Even though nearly all colorectal cancers contain mutations in β-catenin or APC/Axin, epigenetic silencing of Sox7 was still observed. These data suggest that Sox7 is a tumor suppressor that functions as an independent checkpoint for β-catenin transcriptional activity. Inactivation of Sox7 could promote the development of a majority of colorectal tumors and approximately half of prostate tumors.
doi:10.1158/1541-7786.MCR-07-2175
PMCID: PMC2652859  PMID: 18819930
WNT signaling; promoter methylation; tumor suppressor; chromosome 8p; Sox7; prostate cancer; colorectal cancer; β-catenin

Results 1-4 (4)