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Phosphorylation-dependent activation of peroxisome proliferator protein PEX11 controls peroxisome abundance.

ABSTRACT: Peroxisomes are dynamic organelles that divide continuously in growing cell cultures and expand extensively in lipid-rich medium. Peroxisome population control is achieved in part by Pex11p-dependent regulation of peroxisome size and number. Although the production of Pex11p in yeast is tightly linked to peroxisome biogenesis by transcriptional regulation of the PEX11 gene, it remains unclear if and how Pex11p activity could be modulated by rapid signaling. We report the reversible phosphorylation of Saccharomyces cerevisiae Pex11p in response to nutritional cues and delineate a mechanism for phosphorylation-dependent activation of Pex11p through the analysis of phosphomimicking mutants. Peroxisomal phenotypes in the PEX11-A and PEX11-D strains expressing constitutively dephosphorylated and phosphorylated forms of Pex11p resemble those of PEX11 gene knock-out and overexpression mutants, although PEX11 transcript and Pex11 protein levels remain unchanged. We demonstrate functional inequality and differences in subcellular localization of the Pex11p forms. Pex11Dp promotes peroxisome fragmentation when reexpressed in cells containing induced peroxisomes. Pex11p translocates between endoplasmic reticulum and peroxisomes in a phosphorylation-dependent manner, whereas Pex11Ap and Pex11Dp are impaired in trafficking and constitutively associated with mature and proliferating peroxisomes, respectively. Overexpression of cyclin-dependent kinase Pho85p results in hyperphosphorylation of Pex11p and peroxisome proliferation. This study provides the first evidence for control of peroxisome dynamics by phosphorylation-dependent regulation of a peroxin.

SUBMITTER: Knoblach B

PROVIDER: S-EPMC2825462 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Phosphorylation-dependent activation of peroxisome proliferator protein PEX11 controls peroxisome abundance.

Knoblach Barbara B Rachubinski Richard A RA

The Journal of biological chemistry 20091222 9

Peroxisomes are dynamic organelles that divide continuously in growing cell cultures and expand extensively in lipid-rich medium. Peroxisome population control is achieved in part by Pex11p-dependent regulation of peroxisome size and number. Although the production of Pex11p in yeast is tightly linked to peroxisome biogenesis by transcriptional regulation of the PEX11 gene, it remains unclear if and how Pex11p activity could be modulated by rapid signaling. We report the reversible phosphorylati ...[more]

PMID: 20028986

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Project description:BackgroundProstate cancer (PC) remains a leading cause of cancer mortality and the most successful chemopreventative and treatment strategies for PC come from targeting the androgen receptor (AR). Although AR plays a key role, it is likely that other molecular pathways also contribute to PC, making it essential to identify and develop drugs against novel targets. Recent studies have identified peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that regulates fatty acid (FA) metabolism, as a novel target in PC, and suggest that inhibitors of PPARγ could be used to treat existing disease. We hypothesized that PPARγ acts through AR-dependent and independent mechanisms to control PC development and growth and that PPARγ inhibition is a viable PC treatment strategy.MethodsImmunohistochemistry was used to determine expression of PPARү in a cohort of patients with PC. Standard molecular techniques were used to investigate the PPARү signaling in PC cells as well a xenograft mouse model to test PPARү inhibition in vivo. Kaplan-Meier curves were created using cBioportal.ResultsWe confirmed the expression of PPARү in human PC. We then showed that small molecule inhibition of PPARγ decreases the growth of AR-positive and -negative PC cells in vitro and that T0070907, a potent PPARγ antagonist, significantly decreased the growth of human PC xenografts in nude mice. We found that PPARγ antagonists or small interfering RNA (siRNA) do not affect mitochondrial activity nor do they cause apoptosis; instead, they arrest the cell cycle. In AR-positive PC cells, antagonists and siRNAs reduce AR transcript and protein levels, which could contribute to growth inhibition. AR-independent effects on growth appear to be mediated by effects on FA metabolism as the specific FASN inhibitor, Fasnall, inhibited PC cell growth but did not have an additive effect when combined with PPARγ antagonists. Patients with increased PPARү target gene expression, but not alterations in PPARү itself, were found to have significantly worse overall survival.ConclusionsHaving elucidated the direct cancer cell effects of PPARγ inhibition, our studies have helped to determine the role of PPARγ in PC growth, and support the hypothesis that PPARγ inhibition is an effective strategy for PC treatment.

Dataset Information

Phosphorylation-dependent activation of peroxisome proliferator protein PEX11 controls peroxisome abundance.

Publications

Phosphorylation-dependent activation of peroxisome proliferator protein PEX11 controls peroxisome abundance.

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