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ABSTRACT: The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ∼50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer.
Cancer Research 10/2010; 70(21):8517-25. · 7.86 Impact Factor
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ABSTRACT: Mutations in presenilin 1 (PS1) lead to dominant inheritance of early onset familial Alzheimer disease (FAD). These mutations are known to alter the gamma-secretase cleavage of the amyloid precursor protein, resulting in increased ratio of Abeta42/Abeta40 and accelerated amyloid plaque pathology in transgenic mouse models. To investigate the factors that drive the Abeta42/Abeta40 ratio and amyloid pathogenesis and to investigate the possible interactions between wild-type and FAD mutant PS1, which are co-expressed in transgenic animals, we expressed the PS1 M146V knock-in allele either on wild-type PS1 (PS1M146V/+) or PS1 null (PS1M146V/-) background and crossed these alleles with the Tg2576 APP transgenic mice. Introduction of the PS1 M146V mutation on Tg2576 background resulted in earlier onset of plaque pathology. Surprisingly, removing the wild-type PS1 in the presence of the PS1 M146V mutation (PS1M146V/-) greatly exacerbated the amyloid burden; and this was attributed to a reduction of gamma-secretase activity rather than an increase in Abeta42. Our findings establish a protective role of the wild-type PS1 against the FAD mutation-induced amyloid pathology through a partial loss-of-function mechanism.
Journal of Biological Chemistry 07/2006; 281(22):15330-6. · 4.77 Impact Factor
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Dongming Cai,
Minghao Zhong, Runsheng Wang,
William J Netzer,
Dennis Shields,
Hui Zheng,
Sangram S Sisodia,
David A Foster,
Fred S Gorelick,
Huaxi Xu,
Paul Greengard
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ABSTRACT: Presenilins (PS1/PS2) regulate proteolysis of beta-amyloid precursor protein (betaAPP) and affect its intracellular trafficking. Here, we demonstrate that a PS1-interacting protein, phospholipase D1 (PLD1), affects intracellular trafficking of betaAPP. Overexpression of PLD1 in PS1wt cells promotes generation of betaAPP-containing vesicles from the trans-Golgi network. Conversely, inhibition of PLD1 activity by 1-butanol decreases betaAPP trafficking in both wt and PS1-deficient cells. The subcellular localization of PLD1 is altered, and PLD enzymatic activity is reduced in cells expressing familial Alzheimer's disease (FAD) PS1 mutations compared with PS1wt cells. Overexpression of wt, but not catalytically inactive, PLD1 increases budding of betaAPP-containing vesicles from the trans-Golgi network in FAD mutant cells. Surface delivery of betaAPP is also increased by PLD1 in these cells. The impaired neurite outgrowth capacity in FAD mutant neurons was corrected by introducing PLD1 into these cells. The results indicate that PLD1 may represent a therapeutic target for rescuing compromised neuronal function in AD.
Proceedings of the National Academy of Sciences 03/2006; 103(6):1936-40. · 9.68 Impact Factor
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Dongming Cai,
Minghao Zhong, Runsheng Wang,
William J. Netzer,
Dennis Shields,
Hui Zheng,
Sangram S. Sisodia,
David A. Foster,
Fred S. Gorelick,
Huaxi Xu,
Paul Greengard
[show abstract]
[hide abstract]
ABSTRACT: Presenilins (PS1/PS2) regulate proteolysis of β-amyloid precursor protein (βAPP) and affect its intracellular trafficking.
Here, we demonstrate that a PS1-interacting protein, phospholipase D1 (PLD1), affects intracellular trafficking of βAPP. Overexpression
of PLD1 in PS1wt cells promotes generation of βAPP-containing vesicles from the trans-Golgi network. Conversely, inhibition
of PLD1 activity by 1-butanol decreases βAPP trafficking in both wt and PS1-deficient cells. The subcellular localization
of PLD1 is altered, and PLD enzymatic activity is reduced in cells expressing familial Alzheimer’s disease (FAD) PS1 mutations
compared with PS1wt cells. Overexpression of wt, but not catalytically inactive, PLD1 increases budding of βAPP-containing
vesicles from the trans-Golgi network in FAD mutant cells. Surface delivery of βAPP is also increased by PLD1 in these cells.
The impaired neurite outgrowth capacity in FAD mutant neurons was corrected by introducing PLD1 into these cells. The results
indicate that PLD1 may represent a therapeutic target for rescuing compromised neuronal function in AD.
Proceedings of the National Academy of Sciences 02/2006; 103(6):1936-1940. · 9.68 Impact Factor
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ABSTRACT: Presenilins (PS) are required for gamma-secretase cleavage of multiple type I membrane proteins including the amyloid precursor protein and Notch and also have been implicated in regulating intracellular protein trafficking and turnover. Using genetic and pharmacological approaches, we reveal here a unique function of PS in the pigmentation of retinal pigment epithelium and epidermal melanocytes. PS deficiency leads to aberrant accumulation of tyrosinase (Tyr)-containing 50-nm post-Golgi vesicles that are normally destined to melanosomes. This trafficking is gamma-secretase-dependent, and abnormal localization of Tyr in the absence of PS is accompanied by the simultaneous accumulation of its C-terminal fragment. Furthermore, we show that the PS1M146V familial Alzheimer's disease mutation exhibits a partial loss-of-function in pigment synthesis. Our results identify Tyr and related proteins as physiological substrates of PS and link gamma-secretase activity with intracellular protein transport.
Proceedings of the National Academy of Sciences 02/2006; 103(2):353-8. · 9.68 Impact Factor
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Dongming Cai,
Jae Yoon Leem,
Jeffrey P Greenfield,
Pei Wang,
Benny S Kim, Runsheng Wang,
Kryslaine O Lopes,
Seong-Hun Kim,
Hui Zheng,
Paul Greengard,
Sangram S Sisodia,
Gopal Thinakaran,
Huaxi Xu
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ABSTRACT: Presenilins (PS1/PS2) play a critical role in proteolysis of beta-amyloid precursor protein (beta APP) to generate beta-amyloid, a peptide important in the pathogenesis of Alzheimer's disease. Nevertheless, several regulatory functions of PS1 have also been reported. Here we demonstrate, in neuroblastoma cells, that PS1 regulates the biogenesis of beta APP-containing vesicles from the trans-Golgi network and the endoplasmic reticulum. PS1 deficiency or the expression of loss-of-function variants leads to robust vesicle formation, concomitant with increased maturation and/or cell surface accumulation of beta APP. In contrast, release of vesicles containing beta APP is impaired in familial Alzheimer's disease (FAD)-linked PS1 mutant cells, resulting in reduced beta APP delivery to the cell surface. Moreover, diminution of surface beta APP is profound at axonal terminals in neurons expressing a PS1 FAD variant. These results suggest that PS1 regulation of beta APP trafficking may represent an alternative mechanism by which FAD-linked PS1 variants modulate beta APP processing.
Journal of Biological Chemistry 02/2003; 278(5):3446-54. · 4.77 Impact Factor
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Dongming Cai,
Jae Yoon Leem,
Jeffrey P. Greenfield,
Pei Wang,
Benny S. Kim, Runsheng Wang,
Kryslaine O. Lopes,
Seong-Hun Kim,
Hui Zheng,
Paul Greengard,
Sangram S. Sisodia,
Gopal Thinakaran,
Huaxi Xu
[show abstract]
[hide abstract]
ABSTRACT: Presenilins (PS1/PS2) play a critical role in proteolysis of β-amyloid precursor protein (βAPP) to generate β-amyloid, a peptide
important in the pathogenesis of Alzheimer's disease. Nevertheless, several regulatory functions of PS1 have also been reported.
Here we demonstrate, in neuroblastoma cells, that PS1 regulates the biogenesis of βAPP-containing vesicles from thetrans-Golgi network and the endoplasmic reticulum. PS1 deficiency or the expression of loss-of-function variants leads to robust
vesicle formation, concomitant with increased maturation and/or cell surface accumulation of βAPP. In contrast, release of
vesicles containing βAPP is impaired in familial Alzheimer's disease (FAD)-linked PS1 mutant cells, resulting in reduced βAPP
delivery to the cell surface. Moreover, diminution of surface βAPP is profound at axonal terminals in neurons expressing a
PS1 FAD variant. These results suggest that PS1 regulation of βAPP trafficking may represent an alternative mechanism by which
FAD-linked PS1 variants modulate βAPP processing.
Journal of Biological Chemistry 01/2003; 278(5):3446-3454. · 4.77 Impact Factor
