Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

Xie, Yingqiu; Burcu, Mehmet; Linn, Douglas E.; Qiu, Yun

doi:10.1124/mol.109.061713

Cited by 86 publications

(89 citation statements)

References 43 publications

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“…The interaction between ABCA1 and Pim-1 was confirmed by the presence of HA-Pim-1L in immunoprecipitates obtained with anti-FLAG antibody from COS-1 cells expressing 3×FLAG-ABCA1 and HA-Pim-1L ( Figure 3B). Consistent with the previous reports, [29][30][31] in immunocytochemistry, HAPim-1L was detected not only in cytoplasm but also just beneath …”

supporting

confidence: 79%

“…29,31 However, the mechanism responsible differs from that for ABCA1, because Pim-1L-mediated phosphorylation assists the trafficking of ABCG2 to the plasma membrane by promoting homodimer formation, and that of ABCB1 by inhibiting proteosomal degradation in the endoplasmic reticulum.…”

mentioning

confidence: 99%

“…28 The 2 isoforms of Pim-1 differ in cellular localization in that Pim-1S is present in the cytosol and nucleus, whereas Pim-1L is primarily localized to the plasma membrane. [29][30][31] Therefore, Pim-1S and Pim-1L are considered to regulate distinct substrates. Although the cellular function of Pim-1L has been much less extensively studied than that of Pim-1S, Pim-1L is suggested to form a complex with other cellular components.…”

mentioning

confidence: 99%

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Pim-1L Protects Cell Surface–Resident ABCA1 From Lysosomal Degradation in Hepatocytes and Thereby Regulates Plasma High-Density Lipoprotein Level

Katsube

Hayashi

Kusuhara

2016

ATVB

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Objective-ATP-binding cassette transporter A1 (ABCA1) exerts an atheroprotective action through the biogenesis of highdensity lipoprotein in hepatocytes and prevents the formation of foam cells from macrophages. Controlling ABCA1 is a rational approach to improving atherosclerotic cardiovascular disease. Although much is known about the regulatory mechanism of ABCA1 synthesis, the molecular mechanism underpinning its degradation remains to be clearly described. Approach and Results-ABCA1 possesses potential sites of phosphorylation by serine/threonine-protein kinase Pim-1 (Pim-1). Pim-1 depletion decreased the expression of cell surface-resident ABCA1 (csABCA1) and apolipoprotein A-I-mediated [ 3 H]cholesterol efflux in the human hepatoma cell line HepG2, but not in peritoneal macrophages from mice. In vitro kinase assay, immunoprecipitation, and immunocytochemistry suggested phosphorylation of csABCA1 by the long form of Pim-1 (Pim-1L). Cell surface biotinylation indicated that Pim-1L inhibited lysosomal degradation of csABCA1 involving the liver X receptor β, which interacts with csABCA1 and thereby protects it from ubiquitination and subsequent lysosomal degradation. Cell surface coimmunoprecipitation with COS-1 cells expressing extracellularly hemagglutinin-tagged ABCA1 showed that Pim-1L-mediated phosphorylation of csABCA1 facilitated the interaction between csABCA1 and liver X receptor β and thereby stabilized the csABCA1-Pim-1L complex. Mice deficient in Pim-1 kinase activity showed lower expression of ABCA1 in liver plasma membranes and lower plasma high-density lipoprotein levels than control mice. Conclusions-Pim-1L protects hepatic csABCA1 from lysosomal degradation by facilitating the physical interaction between csABCA1 and liver X receptor β and subsequent stabilization of the csABCA1-Pim-1L complex and thereby regulates the circulating level of high-density lipoprotein. Our findings may aid the development of high-density lipoproteintargeted therapy. Katsube et al Protection of Hepatic csABCA1 by Pim-1L 2305mechanism underlying the degradation of ABCA1 remains elusive. Although in vitro and animal studies using inhibitors of the protease calpain and proteasome suggest that they cleave and degrade ABCA1, [16][17][18][19] the molecular entity of calpain and the molecular mechanism of the degradation of ABCA1 involving proteasome have not yet been clearly described. On the basis of the report by Hozoji et al 20 that LXRβ interacts with and post-translationally modulates ABCA1, we recently found that LXRβ protects the cell surface-resident ABCA1 (csABCA1) from ubiquitination through its physical interaction with csABCA1 and not through its transcriptional activity, which prevents lysosomal degradation of csABCA1 through the endosomal sorting complex required for transport (ESCRT) system. 21,22 This mechanism mediates ABCA1 degradation independently of the pathway involving calpain and proteasome. To gain further insight into this finding, the current study focuses on phosphorylation because phosphory...

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supporting

confidence: 79%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pim-1L Protects Cell Surface–Resident ABCA1 From Lysosomal Degradation in Hepatocytes and Thereby Regulates Plasma High-Density Lipoprotein Level

Katsube

Hayashi

Kusuhara

2016

ATVB

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“…Pim-1 can also phosphorylate P-glycoprotein (MDR-1 gene product), which results in its protection from ubiquitination and proteasomal degradation. Its inhibition reverses resistance to doxorubicin in ovarian cancer cells that overexpress P-glycoprotein 134 . Experiments that directly link the effects of Pim-1 on NF-κB signaling and increased resistance to cytostatic drugs constitute a valuable and interesting field for further study 117 .…”

mentioning

confidence: 99%

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Doktorova

Hraběta

Khalil

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. Results. Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results. Conclusions. The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development.

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“…In addition to controlling the activities of ABC transporters, regulating the expressions of ABC transporters might broadly represent a more effective approach to overcoming MDR. ABC transporter expression could be generally classified as regulated at the transcriptional level (Scotto, 2003;Callaghan et al, 2008) and by post-translational modifications (Minami et al, 2009;Xie et al, 2010); transcriptional regulation has been a main focus of previous studies (Gu and Manautou, 2010). Many transcriptional factors including NF-B (Bentires-Alj et al, 2003), Y-box binding protein-1 (Shen et al, 2011), activator protein-1 (Bark and Choi, 2010), and hypoxia-inducible factor-1 have been found to bind to the promoter region of the MDR gene to initiate the transcription and expression of ABC transporters.…”

Section: Introductionmentioning

confidence: 99%

Key Role of Nuclear Factor-κB in the Cellular Pharmacokinetics of Adriamycin in MCF-7/Adr Cells: The Potential Mechanism for Synergy with 20(S)-Ginsenoside Rh2

Zhang

Meng²,

Zhou³

et al. 2012

Drug Metab Dispos

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ABSTRACT:We have previously demonstrated that ginsenoside 20(S)-Rh2 is a potent ATP-binding cassette (ABC) B1 inhibitor and explored the cellular pharmacokinetic mechanisms for its synergistic effect on the cytotoxicity of Adriamycin. The present studies were conducted to elucidate the key factors that influenced ABCB1 expression, which could further alter Adriamycin cellular pharmacokinetics. Meanwhile, the influence of 20 (

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Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

Cited by 86 publications

References 43 publications

Pim-1L Protects Cell Surface–Resident ABCA1 From Lysosomal Degradation in Hepatocytes and Thereby Regulates Plasma High-Density Lipoprotein Level

Pim-1L Protects Cell Surface–Resident ABCA1 From Lysosomal Degradation in Hepatocytes and Thereby Regulates Plasma High-Density Lipoprotein Level

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Key Role of Nuclear Factor-κB in the Cellular Pharmacokinetics of Adriamycin in MCF-7/Adr Cells: The Potential Mechanism for Synergy with 20(S)-Ginsenoside Rh2

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