C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

Pawar, Snehalata A.; Sarkar, Tapasree Roy; Balamurugan, Krishnaswamy; Sharan, Shikha; Wang, Jun; Zhang, Youhong; Dowdy, Steven F.; Huang, A-Mei; Sterneck, Esta

doi:10.1073/pnas.0913813107

Cited by 69 publications

(78 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We therefore tested the possibility that the activity of proteasome complex influences the LAG-3 trafficking to the cell surface. Consistent with previous observation, treatment of unstimulated or stimulated LAG-3-overexpressing Jurkat cells with 20 mM MG132 led to an increase in the relative amount of cyclin D1 (22), whereas it had no effect on the total expression levels of LAG-3 (Supplemental Fig. 2C).…”

Section: Resultssupporting

confidence: 78%

Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling

Bae

Lee

Park

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Lymphocyte activation gene-3 (LAG-3; CD223), a structural homolog of CD4, binds to MHC class II molecules. Recent research indicated that signaling mediated by LAG-3 inhibits T cell proliferation, and LAG-3 serves as a key surface molecule for the function of regulatory T cells. Previous reports demonstrated that the majority of LAG-3 is retained in the intracellular compartments and is rapidly translocated to the cell surface upon stimulation. However, the mechanism by which LAG-3 translocates to the cell surface was unclear. In this study, we examined the trafficking of human LAG-3 under unstimulated as well as stimulated conditions of T cells. Under the unstimulated condition, the majority of LAG-3 did not reach the cell surface, but rather degraded within the lysosomal compartments. After stimulation, the majority of LAG-3 translocated to the cell surface without degradation in the lysosomal compartments. Results indicated that the cytoplasmic domain without Glu-Pro repetitive sequence is critical for the translocation of LAG-3 from lysosomal compartments to the cell surface. Moreover, protein kinase C signaling leads to the translocation of LAG-3 to the cell surface. However, two potential serine phosphorylation sites from the LAG-3 cytoplasmic domain are not involved in the translocation of LAG-3. These results clearly indicate that LAG-3 trafficking from lysosomal compartments to the cell surface is dependent on the cytoplasmic domain through protein kinase C signaling in activated T cells.

show abstract

Section: Resultssupporting

confidence: 78%

Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling

Bae

Lee

Park

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…In line with previous reports (7), we also found that statin (30 min) decreased the level of cyclin D1 by 29% (data not shown). These data are in line with a previously shown rapid degradation of cyclin D1 (34,35).…”

Section: Atp and Atorvastatin Rapidlysupporting

confidence: 81%

“…Both GSK-3␤-dependent and -independent mechanisms for cyclin D1 degradation have been described (35), and our model might be particular useful for clarifying their mutual relationship. It is clear, however, that a rapid down-regulation of cyclin D1 leads to G 1 arrest (34,35). Further studies may, for example, show if this effect can explain an ATP-dependent prevention of metastatic spread seen in mammary cancer (42).…”

Section: Discussionmentioning

confidence: 99%

“…Here we show that the depletion of pAkt was associated with a nuclear translocation of PCNA and binding to p21 cip1 . Both of these proteins bind cyclin D1 (35,41), and drug-induced cyclin D1 degradation mechanisms are not fully understood (34), so additional studies seem warranted. Both GSK-3␤-dependent and -independent mechanisms for cyclin D1 degradation have been described (35), and our model might be particular useful for clarifying their mutual relationship.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Purinergic Receptor-mediated Rapid Depletion of Nuclear Phosphorylated Akt Depends on Pleckstrin Homology Domain Leucine-rich Repeat Phosphatase, Calcineurin, Protein Phosphatase 2A, and PTEN Phosphatases

Mistafa¹,

Ghalali²,

Kadekar

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Akt is an important oncoprotein, and data suggest a critical role for nuclear Akt in cancer development. We have previously described a rapid (3-5 min) and P2X7-dependent depletion of nuclear phosphorylated Akt (pAkt) and effects on downstream targets, and here we studied mechanisms behind the pAkt depletion. We show that cholesterol-lowering drugs, statins, or extracellular ATP, induced a complex and coordinated response in insulin-stimulated A549 cells leading to depletion of nuclear pAkt. It involved protein/lipid phosphatases PTEN, pleckstrin homology domain leucine-rich repeat phosphatase (PHLPP1 and -2), protein phosphatase 2A (PP2A), and calcineurin. We employed immunocytology, immunoprecipitation, and proximity ligation assay techniques and show that PHLPP and calcineurin translocated to the nucleus and formed complexes with Akt within 3 min. Also PTEN translocated to the nucleus and then co-localized with pAkt close to the nuclear membrane. An inhibitor of the scaffolding immunophilin FK506-binding protein 51 (FKBP51) and calcineurin, FK506, prevented depletion of nuclear pAkt. Furthermore, okadaic acid, an inhibitor of PP2A, prevented the nuclear pAkt depletion. Chemical inhibition and siRNA indicated that PHLPP, PP2A, and PTEN were required for a robust depletion of nuclear pAkt, and in prostate cancer cells lacking PTEN, transfection of PTEN restored the statin-induced pAkt depletion. The activation of protein and lipid phosphatases was paralleled by a rapid proliferating cell nuclear antigen (PCNA) translocation to the nucleus, a PCNAp21 cip1 complex formation, and cyclin D1 degradation. We conclude that these effects reflect a signaling pathway for rapid depletion of pAkt that may stop the cell cycle.The serine/threonine kinase Akt is a central regulator of apoptosis and cell growth and is activated by insulin, growth factors, and cellular stress. Many studies indicate a key role for Akt in carcinogenesis and as a target for therapeutic agents (1-4). 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, statins, have anticancer properties (5), and we have shown that statins decrease levels of phosphorylated Akt (pAkt) 3 in lung and pancreatic cancer cells (6 -9). A conspicuous finding was that dephosphorylation of nuclear Akt was induced within minutes and that this effect was associated with inhibited cell proliferation. Extracellular ATP also induced nuclear pAkt depletion, and several lines of evidence indicated that the rapid pAkt depletion was mediated by the purinergic receptor P2X7 (7,8).A family of protein phosphatases, pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP), was identified as a phosphatase for Akt (10). Two isoforms, PHLPP1 and PHLPP2, have been shown to dephosphorylate distinct Akt isoforms, at one (Ser 473 ) of two phosphorylation sites required for activation (11). This dephosphorylation is regulated by the immunophilin FKBP51 (FK506-binding protein 51), which acts as scaffolding protein for Akt and PHLPP (12). Other phosphatases shown to dephosphoryl...

show abstract

“…In contrast, the minor tumor cell subset predominantly contained CDC27 and PABPC1 mutations (Figure 3). Concordantly, both CDC27 and PABPC1 have been reported as tumor suppressors in other cancer types [18,19]. The absence of TP53 and APC mutations as well as other genetic alterations in the minor cell subset strongly supports that these The density distribution of SMAFS of 21 whole-tissue exomesequenced colon cancer was analyzed by kernel density estimate (KDE).…”

Section: Distinct Cellular Origins Of Two Subsets Revealed By Clustermentioning

confidence: 79%

Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing

et al. 2014

Self Cite

View full text Add to dashboard Cite

Single-cell sequencing is a powerful tool for delineating clonal relationship and identifying key driver genes for personalized cancer management. Here we performed single-cell sequencing analysis of a case of colon cancer. Population genetics analyses identified two independent clones in tumor cell population. The major tumor clone harbored APC and TP53 mutations as early oncogenic events, whereas the minor clone contained preponderant CDC27 and PABPC1 mutations. The absence of APC and TP53 mutations in the minor clone supports that these two clones were derived from two cellular origins. Examination of somatic mutation allele frequency spectra of additional 21 wholetissue exome-sequenced cases revealed the heterogeneity of clonal origins in colon cancer. Next, we identified a mutated gene SLC12A5 that showed a high frequency of mutation at the single-cell level but exhibited low prevalence at the population level. Functional characterization of mutant SLC12A5 revealed its potential oncogenic effect in colon cancer. Our study provides the first exome-wide evidence at single-cell level supporting that colon cancer could be of a biclonal origin, and suggests that low-prevalence mutations in a cohort may also play important protumorigenic roles at the individual level.

show abstract

C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

Cited by 69 publications

References 41 publications

Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling

Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling

Purinergic Receptor-mediated Rapid Depletion of Nuclear Phosphorylated Akt Depends on Pleckstrin Homology Domain Leucine-rich Repeat Phosphatase, Calcineurin, Protein Phosphatase 2A, and PTEN Phosphatases

Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing

Contact Info

Product

Resources

About