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Cdh1, a substrate recruiting component of APC/C ubiquitin E3 ligase, specifically interacts with PTEN and promotes its removal from chromatin

Choi, Byeong Hyeok; Pagano, Michele; Huang, Chuanshu; Dai, Wei
A pool of PTEN localizes to the nucleus. However, the exact mechanism by which nuclear PTEN is regulated remains unclear. We have recently reported that Plk1 specifically phosphorylates PTEN on S380 during mitosis. Here we report that PTEN also localized to chromatin and that chromatin PTEN was removed by a proteasome-dependent process during mitotic exit. Pulldown analysis revealed that Cdh1, but not Cdc20, was significantly associated with PTEN. Cdh1 interacted with PTEN via two separate domains and their interaction was enhanced by MG132, a proteasome inhibitor. Cdh1 negatively controlled the stability of chromatin PTEN by polyubiquitination. Phosphorylation of PTEN on S380 impaired its interaction with Cdh1, thus positively regulating PTEN stability on chromatin. Significantly, The interaction of PTEN with Cdh1 was phosphatase-independent and Cdh1 knockdown via RNAi led to significant accumulation of chromatin PTEN, delaying mitotic exit. Combined, our studies identify Cdh1 as an important regulator of nuclear/chromatin PTEN during mitosis.
PMCID:4067225
PMID: 24811168
ISSN: 0021-9258
CID: 988602

Plk1 phosphorylates PTEN and regulates its mitotic activity during the cell cycle

Choi, Byeong; Pagano, Michele; Dai, Wei
PTEN is a well-known tumor suppressor through the negative regulation of the PI3K signaling pathway. Here we report that PTEN plays an important role in regulating mitotic timing, which is associated with increased PTEN phosphorylation in the C-terminal tail and its localization to chromatin. Pull-down analysis revealed that Plk1 physically interacted with PTEN. Biochemical studies showed that Plk1 phosphorylates PTEN in vitro in a concentration-dependent manner and that the phosphorylation was inhibited by Bi2635, a Plk1-specific inhibitor. Deletional and mutational analyses identified that Plk1 phosphorylated S380, T382 and T383, but not S385, a cluster of residues known to affect the PTEN stability. Interestingly, a combination of molecular and genetic analyses revealed that only S380 was significantly phosphorylated in vivo and that Plk1 regulated the phosphorylation, which was associated with accumulation of PTEN on chromatin. Moreover, expression of phospho-deficient mutant, but not wild-type PTEN, caused enhanced mitotic exit. Taken together, our studies identify Plk1 as an important regulator of PTEN during the cell cycle.
PMCID:4022876
PMID: 24706748
ISSN: 0021-9258
CID: 988612

Chromatin PTEN is involved in DNA damage response partly through regulating Rad52 sumoylation

Choi, Byeong Hyeok; Chen, Yan; Dai, Wei
A pool of PTEN localizes to the nucleus. However, the exact mechanism of action of nuclear PTEN remains poorly understood. We have investigated PTEN's role during DNA damage response. Here we report that PTEN undergoes chromatin translocation after DNA damage, and that its translocation is closely associated with its phosphorylation on S366/T370 but not on S380. Deletional analysis reveals that the C2 domain of PTEN is responsible for its nuclear translocation after exposure to genotoxin. Both casein kinase 2 and GSK3beta are involved in the phosphorylation of the S366/T370 epitope, as well as PTEN's association with chromatin after DNA damage. Significantly, PTEN specifically interacts with Rad52 and colocalizes with Rad52, as well as gammaH2AX, after genotoxic stress. Moreover, PTEN is involved in regulating Rad52 sumoylation. Combined, our studies strongly suggest that nuclear/chromatin PTEN mediates DNA damage repair through interacting with and modulating the activity of Rad52.
PMCID:3895432
PMID: 24047694
ISSN: 1551-4005
CID: 614282

Analysis for the potential of polystyrene and TiO2 nanoparticles to induce skin irritation, phototoxicity, and sensitization

Park, Yoon-Hee; Jeong, Sang Hoon; Yi, Sang Min; Choi, Byeong Hyeok; Kim, Yu-Ri; Kim, In-Kyoung; Kim, Meyoung-Kon; Son, Sang Wook
The human skin equivalent model (HSEM) is well known as an attractive alternative model for evaluation of dermal toxicity. However, only limited data are available on the usefulness of a HSEM for nanotoxicity testing. This study was designed to investigate cutaneous toxicity of polystyrene and TiO2 nanoparticles using cultured keratinocytes, a HSEM, and an animal model. In addition, we also evaluated the skin sensitization potential of nanoparticles using a local lymph node assay with incorporation of BrdU. Findings from the present study indicate that polystyrene and TiO2 nanoparticles do not induce phototoxicity, acute cutaneous irritation, or skin sensitization. Results from evaluation of the HSEMs correspond well with those from animal models. Our findings suggest that the HSEM might be a useful alternative model for evaluation of dermal nanotoxicity.
PMID: 21664450
ISSN: 1879-3177
CID: 4957352

Oxidative stress and apoptosis induced by ZnO nanoparticles in HaCaT cells

Bae, Hyun Cheol; Ryu, Hwa Jung; Jeong, Sang Hoon; Lee, Eun Young; Park, Yoon-Hee; Lee, Kyung Goo; Choi, Byeong Hyeok; Maeng, Eun Ho; Kim, Meyoung-Kon; Son, Sang Wook
ISI:000298789700001
ISSN: 1738-642x
CID: 4958522

Assessment of the skin irritation potential of quantum dot nanoparticles using a human skin equivalent model [Letter]

Jeong, Sang Hoon; Park, Yoon Hee; Choi, Byeong Hyeok; Kim, Jin Ho; Sohn, Kyung Hee; Park, Kui Lea; Kim, Meyoung-Kon; Son, Sang Wook
PMID: 20619609
ISSN: 1873-569x
CID: 4957342

Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1

Choi, Byeong Hyeok; Kim, Chang Gun; Lim, Yoongho; Lee, Young Han; Shin, Soon Young
Klotho is an antiaging gene involved in the suppression of several age-related phenotypes, but few studies have examined the mechanism underlying the regulation of human Klotho gene expression. In this study, we investigated the transcriptional regulation of the Klotho gene by epidermal growth factor (EGF) in HEK293 human embryonic kidney cells. By using serial deletion constructs of the promoter, we identified a proximal 45 bp (-90 to -45) region responsible for EGF-induced promoter activity. The Egr-1-binding motif is located within this region. Forced expression of Egr-1 stimulated Klotho gene promoter activity. A point mutation in the Egr-1-binding motif abrogated promoter inducibility by EGF or ectopic Egr-1 expression. Knockdown of Egr-1 by expression of small interfering RNA (siRNA) attenuated EGF-induced Klotho promoter activity. Further analysis showed that the Ras/MEK/Erk signaling cascade is involved in EGF-induced activation of the Klotho promoter. We conclude that the Klotho gene is activated by EGF in HEK293 cells.
PMID: 19913601
ISSN: 1879-0038
CID: 4957332

Assessment of dermal toxicity of nanosilica using cultured keratinocytes, a human skin equivalent model and an in vivo model

Park, Yoon-Hee; Kim, Ji Na; Jeong, Sang Hoon; Choi, Jae Eun; Lee, Seung-Ho; Choi, Byeong Hyeok; Lee, Jung Pyo; Sohn, Kyung Hee; Park, Kui Lea; Kim, Meyoung-Kon; Son, Sang Wook
Assessments of skin irritation potentials are important aspects of the development of nanotechnology. Nanosilica is currently being widely used for commercial purposes, but little literature is available on its skin toxicity and irritation potential. This study was designed to determine whether nanosilica has the potential to cause acute cutaneous toxicity, using cultured HaCaT keratinocytes (CHK), a human skin equivalent model (HSEM), and invivo model. Nanosilica was characterized by scanning electron microscopy. We evaluated the cytotoxic effects of nanosilica on CHKs and the HSEM. In addition, we also investigated whether two commercially available nanosilicas with different sizes (7 and 10-20 nm) have different effects. To confirm invitro results, we evaluated the irritation potentials of nanosilicas on rabbit skin. Nanosilicas reduced the cell viabilities of CHKs in a dose-dependent manner. However, the HSEM revealed no irritation at 500 microg/ml of nanosilica. Furthermore, this result concurred with Draize skin irritation test findings. The present study data indicate that nanosilica does not cause acute cutaneous irritation. Furthermore, this study shows that the HSEM used provides more useful screening data than the conventional cell culture model on the relative toxicities of NPs.
PMID: 19850098
ISSN: 1879-3185
CID: 4957322

p21 Waf1/Cip1 expression by curcumin in U-87MG human glioma cells: role of early growth response-1 expression

Choi, Byeong Hyeok; Kim, Chang Gun; Bae, Young-Seuk; Lim, Yoongho; Lee, Young Han; Shin, Soon Young
Curcumin, a natural compound, is a well-known chemopreventive agent with potent anticarcinogenic activity in a wide variety of tumor cells. Curcumin inhibits cancer cell proliferation in part by suppressing cyclin D1 and inducing expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Both p53-dependent and p53-independent mechanisms regulate p21(Waf1/Cip1) expression, but the mechanism by which curcumin regulates p21(Waf1/Cip1) expression remains unknown. Here, we report that transcription of the p21(Waf1/Cip1) gene is activated by early growth response-1 (Egr-1) independently of p53 in response to curcumin treatment in U-87MG human glioblastoma cells. Egr-1 is a transcription factor that helps regulate differentiation, growth, and apoptosis in many cell types. Egr-1 expression is induced by curcumin through extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK), but not the p38, mitogen-activated protein kinase (MAPK) pathways, which mediate the transactivation of Elk-1. Transient expression of Egr-1 enhanced curcumin-induced p21(Waf1/Cip1) promoter activity, whereas suppression of Egr-1 expression by small interfering RNA abrogated the ability of curcumin to induce p21(Waf1/Cip1) promoter activity. In addition, stable knockdown of Egr-1 expression in U-87MG cells suppressed curcumin-induced p21 expression. Our results indicate that ERK and JNK MAPK/Elk-1/Egr-1 signal cascade is required for p53-independent transcriptional activation of p21(Waf1/Cip1) in response to curcumin in U-87MG human glioblastoma cells.
PMID: 18316600
ISSN: 1538-7445
CID: 4957312

Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NF kappa B pathway

Choi, Byeong Hyeok; Kim, Chang Gun; Lim, Yoongho; Shin, Soon Young; Lee, Young Han
Curcumin, a constituent of turmeric, has anti-inflammatory, anti-carcinogenic, and chemopreventive effects in several animal tumor models. The expression of P-glycoprotein (P-gp), encoded by the mdr gene, is often associated with multidrug resistance (MDR) to unrelated chemotherapeutic drugs in cancer cells. Here, we demonstrate that curcumin down-regulates P-gp expression in multidrug-resistant L1210/Adr cells. Transfection with a series of 5'-deleted constructs of the mdr1b gene promoter indicated that a proximal region between -205 and +42 of the sequence was responsible for the suppression of promoter activity by curcumin. This response might be associated with the inhibition of the phosphatidyinositol 3-kinase (PI3K)/Akt/nuclear factor-kappa B (NF-kappa B) signaling pathway by curcumin. Moreover, curcumin reversed the MDR of the L1210/Adr cells. Thus, curcumin can contribute to the reversal of the MDR phenotype, probably due to the suppression of P-gp expression via the inhibition of the PI3K/Akt/NF-kappa B signaling pathway.
PMID: 18006147
ISSN: 0304-3835
CID: 4957302