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Kai Yang - One of the best experts on this subject based on the ideXlab platform.

  • Loss of the clock gene PER1 promotes oral squamous cell carcinoma progression via the AKT/mTOR pathway.
    Cancer science, 2020
    Co-Authors: Guojun Yang, Hong Tang, Yixin Yang, Kai Yang
    Abstract:

    Current studies have shown that the clock gene Period 1 (PER1) is downregulated in various tumors and plays an important role in promoting tumor progression. However, the biological functions and mechanism of PER1 in tumors remain largely unknown. In this study, 86 specimens of oral squamous cell carcinoma (OSCC) tissues and adjacent noncancerous tissues were collected to determine the PER1 expression level and the clinical significance of PER1 expression. PER1 was stably inhibited or overexpressed in OSCC cells to investigate its function and mechanism in vitro and in vivo. We found that PER1 was remarkably downregulated in OSCC and that low PER1 expression was significantly associated with TNM clinical stage and poor prognosis of OSCC patients. PER1 overexpression in SCC15 OSCC cells (PER1-OE SCC15 cells) significantly promoted autophagy and apoptosis while inhibiting proliferation and the AKT/mTOR pathway. However, the results obtained in PER1-silenced TSCCA OSCC cells were opposite those obtained in PER1-OE SCC15 cells. After addition of the AKT activator SC79 to PER1-OE SCC15 cells, the increased autophagy and apoptosis as well as decreased proliferation were remarkably rescued. Furthermore, increased apoptosis was significantly rescued in PER1-OE SCC15 cells treated with the autophagy inhibitor autophinib. In vivo tumorigenicity assays also confirmed that PER1 overexpression suppressed tumor growth. Taken together, our findings demonstrate for the first time that PER1 promotes OSCC progression by inhibiting autophagy-mediated cell apoptosis and enhancing cell proliferation in an AKT/mTOR pathway-dependent manner, and PER1 could be used as a valuable therapeutic target for OSCC.

  • The clock gene PER1 plays an important role in regulating the clock gene network in human oral squamous cell carcinoma cells.
    Oncotarget, 2016
    Co-Authors: Qin Zhao, Gang Zheng, Kai Yang
    Abstract:

    // Qin Zhao 1 , Gang Zheng 2 , Kai Yang 1 , Yi-ran Ao 1 , Xiao-li Su 1 , Yu Li 3 , Xiao-qiang Lv 1 1 Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuzhong District, Chongqing 400016, China 2 Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, China 3 Department of Pathology, Chongqing Medical University, Chongqing 400016, China Correspondence to: Kai Yang, email: cqfyyk@hotmail.com Keywords: circadian clock, oral cancer, PER1, gene Received: June 20, 2016     Accepted: August 26, 2016     Published: September 02, 2016 ABSTRACT The various clock genes in normal cells, through their interaction, establish a number of positive and negative feedback loops that compose a network structure. These genes play an important role in regulating normal physiological activities. The expression of clock gene PER1 is decreased in many types of cancer. PER1 is highly correlated with the initiation and progression of cancer by regulating numerous downstream genes. However, it is still unclear whether the lower expression of PER1 in cancer can influence the expression of other clock genes in the clock gene network. In this study, we used short hairpin RNA interference to knock down PER1 effectively in SCC15 human oral squamous cell carcinoma cells. These cancer cells later were subcutaneously injected into the back of nude mice. We discovered that after PER1 knockdown, apoptosis was decreased and cell proliferation and in vivo tumor formation were enhanced. Quantitative real-time PCR result indicated that in vitro and in vivo cancer cells after PER1 knockdown, PER2, DEC1, DEC2, CRY1, CRY2 and NPAS2 were significantly down-regulated at the mRNA level, while PER3 , TIM , RORα and REV-ERBα were significantly up-regulated. It prompts that the role of PER1 in carcinogenesis is exerted not only by regulating downstream genes, but also through the synergistic dysregulation of many other clock genes in the clock gene network.

  • the important tumor suppressor role of PER1 in regulating the cyclin cdk cki network in scc15 human oral squamous cell carcinoma cells
    OncoTargets and Therapy, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang
    Abstract:

    BACKGROUND Accumulating evidence suggests that the abnormal expression of the circadian clock gene PER1 is closely related to the development and progression of cancer. However, the exact molecular mechanism by which the abnormal expression of PER1 induces carcinogenesis is unclear. This study was conducted to investigate the alterations in downstream cell cycle genes, cell cycle distribution, cell proliferation, apoptosis, and in vivo tumorigenicity in SCC15 oral squamous cell carcinoma cells after PER1 downregulation. MATERIALS AND METHODS A stable SCC15 cell line was established to constitutively express shRNA targeting PER1. Quantitative real-time polymerase chain reaction (PCR) and Western blot analyses were conducted to estimate PER1 mRNA and protein expression. The expression of PER1, P53, CyclinD1, CyclinE, CyclinA2, CyclinB1, cyclin-dependent kinase (CDK) 1, CDK2, CDK4, CDK6, P16, P21, WEE1, and CDC25 mRNA was detected by quantitative real-time PCR. Cell cycle distribution, cell proliferation, and apoptosis were determined by flow cytometry. The in vivo tumorigenicity of SCC15 cells was evaluated in female BALB/c nu/nu mice. RESULTS PER1 downregulation resulted in significantly increased mRNA expression levels of CyclinD1, CyclinE, CyclinB1, CDK1, and WEE1 (P<0.05), and significantly decreased mRNA expression levels of P53, CyclinA2, P16, P21, and CDC25 (P<0.05) compared to control cells. Additionally, PER1 downregulation led to significantly fewer cells in S phase (P<0.05), but significantly more cells in G2/M phase (P<0.05) compared to the control group. After PER1 downregulation, the cell proliferation index was significantly higher (P<0.05), and the apoptotic index was significantly lower (P<0.05). The in vivo tumorigenicity of SCC15 cells was significantly enhanced by PER1 downregulation (P<0.05). CONCLUSION PER1 is an important tumor suppressor gene which acts by regulating the Cyclin-CDK-cyclin-dependent kinase inhibitor regulatory network. An in-depth characterization of this gene may further illuminate the molecular mechanisms responsible for the development and progression of cancer, thus providing novel molecular targets for cancer treatment.

  • The important tumor suppressor role of PER1 in regulating the cyclin–CDK–CKI network in SCC15 human oral squamous cell carcinoma cells
    OncoTargets and therapy, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang
    Abstract:

    BACKGROUND Accumulating evidence suggests that the abnormal expression of the circadian clock gene PER1 is closely related to the development and progression of cancer. However, the exact molecular mechanism by which the abnormal expression of PER1 induces carcinogenesis is unclear. This study was conducted to investigate the alterations in downstream cell cycle genes, cell cycle distribution, cell proliferation, apoptosis, and in vivo tumorigenicity in SCC15 oral squamous cell carcinoma cells after PER1 downregulation. MATERIALS AND METHODS A stable SCC15 cell line was established to constitutively express shRNA targeting PER1. Quantitative real-time polymerase chain reaction (PCR) and Western blot analyses were conducted to estimate PER1 mRNA and protein expression. The expression of PER1, P53, CyclinD1, CyclinE, CyclinA2, CyclinB1, cyclin-dependent kinase (CDK) 1, CDK2, CDK4, CDK6, P16, P21, WEE1, and CDC25 mRNA was detected by quantitative real-time PCR. Cell cycle distribution, cell proliferation, and apoptosis were determined by flow cytometry. The in vivo tumorigenicity of SCC15 cells was evaluated in female BALB/c nu/nu mice. RESULTS PER1 downregulation resulted in significantly increased mRNA expression levels of CyclinD1, CyclinE, CyclinB1, CDK1, and WEE1 (P

  • The clock gene PER1 suppresses expression of tumor-related genes in human oral squamous cell carcinoma.
    Oncotarget, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang, Qin Zhao
    Abstract:

    // Han-Xue Li 1 , Xiao-Juan Fu 1 , Kai Yang 1 , Dan Chen 1 , Hong Tang 1 , Qin Zhao 1 1 Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China Correspondence to: Kai Yang, e-mail: cqfyyk@hotmail.com Keywords: oral cancer, tumor, circadian clock, PER1, tumor-related genes Received: October 11, 2015      Accepted: February 20, 2016      Published: March 01, 2016 ABSTRACT Abnormal expression of the clock gene PER1 is highly correlated with carcinogenesis and the development of malignant tumors. Here, we designed short hairpin RNAs (shRNAs) to effectively knock down PER1 in SCC15 human oral squamous cell carcinoma cells. shRNA-mediated PER1 knockdown promoted SCC15 cell growth, proliferation, apoptosis resistance, migration and invasion in vitro . PER1 knockdown also increased the cells’ expression of KI-67, MDM2, BCL-2, MMP2 and MMP9 mRNA, and decreased expression of C-MYC, p53, BAX and TIMP-2 . In BALB/c nu/nu nude mice subcutaneously injected with SCC15 cells, PER1 knockdown in the cells enhanced tumor development, leading to increased tumor weights and volumes. These results suggest that PER1 is an important tumor suppressor gene and may be a useful molecular target for the treatment of cancer.

Hong Tang - One of the best experts on this subject based on the ideXlab platform.

  • Loss of the clock gene PER1 promotes oral squamous cell carcinoma progression via the AKT/mTOR pathway.
    Cancer science, 2020
    Co-Authors: Guojun Yang, Hong Tang, Yixin Yang, Kai Yang
    Abstract:

    Current studies have shown that the clock gene Period 1 (PER1) is downregulated in various tumors and plays an important role in promoting tumor progression. However, the biological functions and mechanism of PER1 in tumors remain largely unknown. In this study, 86 specimens of oral squamous cell carcinoma (OSCC) tissues and adjacent noncancerous tissues were collected to determine the PER1 expression level and the clinical significance of PER1 expression. PER1 was stably inhibited or overexpressed in OSCC cells to investigate its function and mechanism in vitro and in vivo. We found that PER1 was remarkably downregulated in OSCC and that low PER1 expression was significantly associated with TNM clinical stage and poor prognosis of OSCC patients. PER1 overexpression in SCC15 OSCC cells (PER1-OE SCC15 cells) significantly promoted autophagy and apoptosis while inhibiting proliferation and the AKT/mTOR pathway. However, the results obtained in PER1-silenced TSCCA OSCC cells were opposite those obtained in PER1-OE SCC15 cells. After addition of the AKT activator SC79 to PER1-OE SCC15 cells, the increased autophagy and apoptosis as well as decreased proliferation were remarkably rescued. Furthermore, increased apoptosis was significantly rescued in PER1-OE SCC15 cells treated with the autophagy inhibitor autophinib. In vivo tumorigenicity assays also confirmed that PER1 overexpression suppressed tumor growth. Taken together, our findings demonstrate for the first time that PER1 promotes OSCC progression by inhibiting autophagy-mediated cell apoptosis and enhancing cell proliferation in an AKT/mTOR pathway-dependent manner, and PER1 could be used as a valuable therapeutic target for OSCC.

  • the important tumor suppressor role of PER1 in regulating the cyclin cdk cki network in scc15 human oral squamous cell carcinoma cells
    OncoTargets and Therapy, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang
    Abstract:

    BACKGROUND Accumulating evidence suggests that the abnormal expression of the circadian clock gene PER1 is closely related to the development and progression of cancer. However, the exact molecular mechanism by which the abnormal expression of PER1 induces carcinogenesis is unclear. This study was conducted to investigate the alterations in downstream cell cycle genes, cell cycle distribution, cell proliferation, apoptosis, and in vivo tumorigenicity in SCC15 oral squamous cell carcinoma cells after PER1 downregulation. MATERIALS AND METHODS A stable SCC15 cell line was established to constitutively express shRNA targeting PER1. Quantitative real-time polymerase chain reaction (PCR) and Western blot analyses were conducted to estimate PER1 mRNA and protein expression. The expression of PER1, P53, CyclinD1, CyclinE, CyclinA2, CyclinB1, cyclin-dependent kinase (CDK) 1, CDK2, CDK4, CDK6, P16, P21, WEE1, and CDC25 mRNA was detected by quantitative real-time PCR. Cell cycle distribution, cell proliferation, and apoptosis were determined by flow cytometry. The in vivo tumorigenicity of SCC15 cells was evaluated in female BALB/c nu/nu mice. RESULTS PER1 downregulation resulted in significantly increased mRNA expression levels of CyclinD1, CyclinE, CyclinB1, CDK1, and WEE1 (P<0.05), and significantly decreased mRNA expression levels of P53, CyclinA2, P16, P21, and CDC25 (P<0.05) compared to control cells. Additionally, PER1 downregulation led to significantly fewer cells in S phase (P<0.05), but significantly more cells in G2/M phase (P<0.05) compared to the control group. After PER1 downregulation, the cell proliferation index was significantly higher (P<0.05), and the apoptotic index was significantly lower (P<0.05). The in vivo tumorigenicity of SCC15 cells was significantly enhanced by PER1 downregulation (P<0.05). CONCLUSION PER1 is an important tumor suppressor gene which acts by regulating the Cyclin-CDK-cyclin-dependent kinase inhibitor regulatory network. An in-depth characterization of this gene may further illuminate the molecular mechanisms responsible for the development and progression of cancer, thus providing novel molecular targets for cancer treatment.

  • The important tumor suppressor role of PER1 in regulating the cyclin–CDK–CKI network in SCC15 human oral squamous cell carcinoma cells
    OncoTargets and therapy, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang
    Abstract:

    BACKGROUND Accumulating evidence suggests that the abnormal expression of the circadian clock gene PER1 is closely related to the development and progression of cancer. However, the exact molecular mechanism by which the abnormal expression of PER1 induces carcinogenesis is unclear. This study was conducted to investigate the alterations in downstream cell cycle genes, cell cycle distribution, cell proliferation, apoptosis, and in vivo tumorigenicity in SCC15 oral squamous cell carcinoma cells after PER1 downregulation. MATERIALS AND METHODS A stable SCC15 cell line was established to constitutively express shRNA targeting PER1. Quantitative real-time polymerase chain reaction (PCR) and Western blot analyses were conducted to estimate PER1 mRNA and protein expression. The expression of PER1, P53, CyclinD1, CyclinE, CyclinA2, CyclinB1, cyclin-dependent kinase (CDK) 1, CDK2, CDK4, CDK6, P16, P21, WEE1, and CDC25 mRNA was detected by quantitative real-time PCR. Cell cycle distribution, cell proliferation, and apoptosis were determined by flow cytometry. The in vivo tumorigenicity of SCC15 cells was evaluated in female BALB/c nu/nu mice. RESULTS PER1 downregulation resulted in significantly increased mRNA expression levels of CyclinD1, CyclinE, CyclinB1, CDK1, and WEE1 (P

  • The clock gene PER1 suppresses expression of tumor-related genes in human oral squamous cell carcinoma.
    Oncotarget, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang, Qin Zhao
    Abstract:

    // Han-Xue Li 1 , Xiao-Juan Fu 1 , Kai Yang 1 , Dan Chen 1 , Hong Tang 1 , Qin Zhao 1 1 Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China Correspondence to: Kai Yang, e-mail: cqfyyk@hotmail.com Keywords: oral cancer, tumor, circadian clock, PER1, tumor-related genes Received: October 11, 2015      Accepted: February 20, 2016      Published: March 01, 2016 ABSTRACT Abnormal expression of the clock gene PER1 is highly correlated with carcinogenesis and the development of malignant tumors. Here, we designed short hairpin RNAs (shRNAs) to effectively knock down PER1 in SCC15 human oral squamous cell carcinoma cells. shRNA-mediated PER1 knockdown promoted SCC15 cell growth, proliferation, apoptosis resistance, migration and invasion in vitro . PER1 knockdown also increased the cells’ expression of KI-67, MDM2, BCL-2, MMP2 and MMP9 mRNA, and decreased expression of C-MYC, p53, BAX and TIMP-2 . In BALB/c nu/nu nude mice subcutaneously injected with SCC15 cells, PER1 knockdown in the cells enhanced tumor development, leading to increased tumor weights and volumes. These results suggest that PER1 is an important tumor suppressor gene and may be a useful molecular target for the treatment of cancer.

  • Aberrant expression of clock gene period1 and its correlations with the growth, proliferation and metastasis of buccal squamous cell carcinoma.
    PloS one, 2013
    Co-Authors: Ningbo Zhao, Kai Yang, Gen-ling Yang, Dan Chen, Hong Tang, Dan Zhao, Chunrong Zhao
    Abstract:

    Period1 (PER1) is an important core clock gene, which regulates normal cell proliferations and physiological rhythms of human beings. Recent studies have showed aberrant expressions and altered rhythms of PER1 were highly correlated to the carcinogenesis and development of malignant tumors. However, there is no study on the correlation of aberrant expressions and altered rhythms of PER1 with the growth, proliferation and metastasis of buccal squamous cell carcinoma (BSCC). In this study, PER1 and MMP-2 expression in the cancerous and adjacent noncancerous tissues of 38 patients with BSCC and its correlations with patients' clinical pathologic characteristics were investigated. A mouse model of BSCC was also established and mice were sacrificed at 4 different time points in a period of 24 hours. Xenografted tumor weight, proliferation index (PI), and mitotic index (MI) of tumors in the 4 time groups were detected. Results showed that PER1 expression was significantly down-regulated in cancerous tissues of patients with BSCC (P

Michelle L Gumz - One of the best experts on this subject based on the ideXlab platform.

  • transcriptional regulation of nhe3 and sglt1 by the circadian clock protein PER1 in proximal tubule cells
    American Journal of Physiology-renal Physiology, 2015
    Co-Authors: Kristen Solocinski, Jacob Richards, Sean All, Kityan Cheng, Syed J Khundmiri, Michelle L Gumz
    Abstract:

    We have previously demonstrated that the circadian clock protein period (Per)1 coordinately regulates multiple genes involved in Na(+) reabsorption in renal collecting duct cells. Consistent with these results, PER1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. The proximal tubule is responsible for a majority of Na(+) reabsorption. Previous work has demonstrated that expression of Na(+)/H(+) exchanger 3 (NHE3) oscillates with a circadian pattern and Na(+)-glucose cotransporter (SGLT)1 has been demonstrated to be a circadian target in the colon, but whether these target genes are regulated by PER1 has not been investigated in the kidney. The goal of the present study was to determine if PER1 regulates the expression of NHE3, SGLT1, and SGLT2 in the kidney. Pharmacological blockade of nuclear PER1 entry resulted in decreased mRNA expression of SGLT1 and NHE3 but not SGLT2 in the renal cortex of mice. PER1 small interfering RNA and pharmacological blockade of PER1 nuclear entry in human proximal tubule HK-2 cells yielded the same results. Examination of heterogeneous nuclear RNA suggested that the effects of PER1 on NHE3 and SGLT1 expression occurred at the level of transcription. PER1 and the circadian protein CLOCK were detected at promoters of NHE3 and SGLT1. Importantly, both membrane and intracellular protein levels of NHE3 and SGLT1 were decreased after blockade of nuclear PER1 entry. This effect was associated with reduced activity of Na(+)-K(+)-ATPase. These data demonstrate a role for PER1 in the transcriptional regulation of NHE3 and SGLT1 in the kidney.

  • a role for the circadian clock protein PER1 in the regulation of the nacl co transporter ncc and the with no lysine kinase wnk cascade in mouse distal convoluted tubule cells
    Journal of Biological Chemistry, 2014
    Co-Authors: Jacob Richards, Robert S. Hoover, Sean All, Kityan Cheng, Michelle L Gumz
    Abstract:

    It has been well established that blood pressure and renal function undergo circadian fluctuations. We have demonstrated that the circadian protein PER1 regulates multiple genes involved in sodium transport in the collecting duct of the kidney. However, the role of PER1 in other parts of the nephron has not been investigated. The distal convoluted tubule (DCT) plays a critical role in renal sodium reabsorption. Sodium is reabsorbed in this segment through the actions of the NaCl co-transporter (NCC), which is regulated by the with-no-lysine kinases (WNKs). The goal of this study was to test if PER1 regulates sodium transport in the DCT through modulation of NCC and the WNK kinases, WNK1 and WNK4. Pharmacological blockade of nuclear PER1 entry resulted in decreased mRNA expression of NCC and WNK1 but increased expression of WNK4 in the renal cortex of mice. These findings were confirmed by using PER1 siRNA and pharmacological blockade of PER1 nuclear entry in mDCT15 cells, a model of the mouse distal convoluted tubule. Transcriptional regulation was demonstrated by changes in short lived heterogeneous nuclear RNA. Chromatin immunoprecipitation experiments demonstrated interaction of PER1 and CLOCK with the promoters of NCC, WNK1, and WNK4. This interaction was modulated by blockade of PER1 nuclear entry. Importantly, NCC protein expression and NCC activity, as measured by thiazide-sensitive, chloride-dependent 22Na uptake, were decreased upon pharmacological inhibition of PER1 nuclear entry. Taken together, these data demonstrate a role for PER1 in the transcriptional regulation of NCC, WNK1, and WNK4.

  • regulation of ncc and the wnk cascade by the circadian clock protein PER1 in murine distal convoluted tubule cells 1109 5
    The FASEB Journal, 2014
    Co-Authors: Jacob Richards, Robert S. Hoover, Sean All, Kityan Cheng, Michelle L Gumz
    Abstract:

    Blood pressure and renal function undergo circadian fluctuations. We have shown that the circadian protein PER1 regulates genes involved in sodium (Na) transport in the kidney collecting duct, but has not been investigated in other parts of the nephron. The distal convoluted tubule (DCT) plays a critical role in Na reabsorption in the nephron through the actions of the Na-Cl co-transporter (NCC), which is regulated by the with-no-lysine kinases (WNKs). Therefore, we wanted to test the hypothesis that PER1 regulates Na transport in the DCT through modulation of NCC, WNK1 and WNK4. Pharmacological blockade of nuclear PER1 entry resulted in decreased mRNA expression of NCC and WNK1, but increased expression of WNK4 in mouse renal cortex. These findings were confirmed by PER1 siRNA and pharmacological blockade of PER1 nuclear entry in mDCT15 cells, a model of the mouse distal convoluted tubule. Measurement of short-lived hnRNA demonstrated that the effect of PER1 was transcriptional. Chromatin immunoprecipita...

  • a role for the circadian clock protein PER1 in the regulation of aldosterone levels and renal na retention
    American Journal of Physiology-renal Physiology, 2013
    Co-Authors: Jacob Richards, Sean All, Kityan Cheng, George Skopis, Lauren A. Jeffers, Jeanette I Lynch, Charles S Wingo, Michelle L Gumz
    Abstract:

    The circadian clock plays an important role in the regulation of physiological processes, including renal function and blood pressure. We have previously shown that the circadian protein period (Per)1 regulates the expression of multiple Na+ transport genes in the collecting duct, including the α-subunit of the renal epithelial Na+ channel. Consistent with this finding, PER1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. We have also recently demonstrated the potential opposing actions of cryptochrome (Cry)2 on PER1 target genes. Recent work by others has demonstrated that Cry1/2 regulates aldosterone production through increased expression of the adrenal gland-specific rate-limiting enzyme 3β-dehydrogenase isomerase (3β-HSD). Therefore, we tested the hypothesis that PER1 plays a role in the regulation of aldosterone levels and renal Na+ retention. Using RNA silencing and pharmacological blockade of PER1 nuclear entry in the NCI-H295R human adrenal cell line, we showed that PER1 regulates 3β-HSD expression in vitro. These results were confirmed in vivo: mice with reduced levels of PER1 had decreased levels of plasma aldosterone and decreased mRNA expression of 3β-HSD. We postulated that mice with reduced PER1 would have a renal Na+-retaining defect. Indeed, metabolic cage experiments demonstrated that PER1 heterozygotes excreted more urinary Na+ compared with wild-type mice. Taken together, these data support the hypothesis that PER1 regulates aldosterone levels and that PER1 plays an integral role in the regulation of Na+ retention.

  • Role of PER1 and the mineralocorticoid receptor in the coordinate regulation of αENaC in renal cortical collecting duct cells.
    Frontiers in physiology, 2013
    Co-Authors: Jacob Richards, Sean All, Kityan Cheng, Lauren A. Jeffers, Michelle L Gumz
    Abstract:

    Renal function and blood pressure exhibit a circadian pattern of variation, but the molecular mechanism underlying this circadian regulation is not fully understood. We have previously shown that the circadian clock protein PER1 positively regulates the basal and aldosterone-mediated expression of the alpha subunit of the renal epithelial sodium channel (αENaC). The mechanism of this regulation has not been determined however. To further elucidate the mechanism of Mineralocorticoid Receptor (MR) and PER1 action, site-directed mutagenesis, DNA pull-down assays and chromatin immunoprecipitation methods were used to investigate the coordinate regulation of αENaC by PER1 and MR. Mutation of two circadian response E-boxes in the human αENaC promoter abolished both basal and aldosterone-mediated promoter activity. DNA pull down assays demonstrated the interaction of both MR and PER1 with the E-boxes from the αENaC promoter. These observations were corroborated by chromatin immunopreciptation experiments showing increased occupancy of MR and PER1 on an E-box of the αENaC promoter in the presence of aldosterone. This is the first report of an aldosterone-mediated increase in PER1 on a target gene promoter. Taken together, these results demonstrate the novel finding that PER1 and MR mediate the aldosterone response of αENaC through DNA/protein interaction in renal collecting duct cells.

Dan Chen - One of the best experts on this subject based on the ideXlab platform.

  • the important tumor suppressor role of PER1 in regulating the cyclin cdk cki network in scc15 human oral squamous cell carcinoma cells
    OncoTargets and Therapy, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang
    Abstract:

    BACKGROUND Accumulating evidence suggests that the abnormal expression of the circadian clock gene PER1 is closely related to the development and progression of cancer. However, the exact molecular mechanism by which the abnormal expression of PER1 induces carcinogenesis is unclear. This study was conducted to investigate the alterations in downstream cell cycle genes, cell cycle distribution, cell proliferation, apoptosis, and in vivo tumorigenicity in SCC15 oral squamous cell carcinoma cells after PER1 downregulation. MATERIALS AND METHODS A stable SCC15 cell line was established to constitutively express shRNA targeting PER1. Quantitative real-time polymerase chain reaction (PCR) and Western blot analyses were conducted to estimate PER1 mRNA and protein expression. The expression of PER1, P53, CyclinD1, CyclinE, CyclinA2, CyclinB1, cyclin-dependent kinase (CDK) 1, CDK2, CDK4, CDK6, P16, P21, WEE1, and CDC25 mRNA was detected by quantitative real-time PCR. Cell cycle distribution, cell proliferation, and apoptosis were determined by flow cytometry. The in vivo tumorigenicity of SCC15 cells was evaluated in female BALB/c nu/nu mice. RESULTS PER1 downregulation resulted in significantly increased mRNA expression levels of CyclinD1, CyclinE, CyclinB1, CDK1, and WEE1 (P<0.05), and significantly decreased mRNA expression levels of P53, CyclinA2, P16, P21, and CDC25 (P<0.05) compared to control cells. Additionally, PER1 downregulation led to significantly fewer cells in S phase (P<0.05), but significantly more cells in G2/M phase (P<0.05) compared to the control group. After PER1 downregulation, the cell proliferation index was significantly higher (P<0.05), and the apoptotic index was significantly lower (P<0.05). The in vivo tumorigenicity of SCC15 cells was significantly enhanced by PER1 downregulation (P<0.05). CONCLUSION PER1 is an important tumor suppressor gene which acts by regulating the Cyclin-CDK-cyclin-dependent kinase inhibitor regulatory network. An in-depth characterization of this gene may further illuminate the molecular mechanisms responsible for the development and progression of cancer, thus providing novel molecular targets for cancer treatment.

  • The important tumor suppressor role of PER1 in regulating the cyclin–CDK–CKI network in SCC15 human oral squamous cell carcinoma cells
    OncoTargets and therapy, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang
    Abstract:

    BACKGROUND Accumulating evidence suggests that the abnormal expression of the circadian clock gene PER1 is closely related to the development and progression of cancer. However, the exact molecular mechanism by which the abnormal expression of PER1 induces carcinogenesis is unclear. This study was conducted to investigate the alterations in downstream cell cycle genes, cell cycle distribution, cell proliferation, apoptosis, and in vivo tumorigenicity in SCC15 oral squamous cell carcinoma cells after PER1 downregulation. MATERIALS AND METHODS A stable SCC15 cell line was established to constitutively express shRNA targeting PER1. Quantitative real-time polymerase chain reaction (PCR) and Western blot analyses were conducted to estimate PER1 mRNA and protein expression. The expression of PER1, P53, CyclinD1, CyclinE, CyclinA2, CyclinB1, cyclin-dependent kinase (CDK) 1, CDK2, CDK4, CDK6, P16, P21, WEE1, and CDC25 mRNA was detected by quantitative real-time PCR. Cell cycle distribution, cell proliferation, and apoptosis were determined by flow cytometry. The in vivo tumorigenicity of SCC15 cells was evaluated in female BALB/c nu/nu mice. RESULTS PER1 downregulation resulted in significantly increased mRNA expression levels of CyclinD1, CyclinE, CyclinB1, CDK1, and WEE1 (P

  • The clock gene PER1 suppresses expression of tumor-related genes in human oral squamous cell carcinoma.
    Oncotarget, 2016
    Co-Authors: Kai Yang, Dan Chen, Hong Tang, Qin Zhao
    Abstract:

    // Han-Xue Li 1 , Xiao-Juan Fu 1 , Kai Yang 1 , Dan Chen 1 , Hong Tang 1 , Qin Zhao 1 1 Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China Correspondence to: Kai Yang, e-mail: cqfyyk@hotmail.com Keywords: oral cancer, tumor, circadian clock, PER1, tumor-related genes Received: October 11, 2015      Accepted: February 20, 2016      Published: March 01, 2016 ABSTRACT Abnormal expression of the clock gene PER1 is highly correlated with carcinogenesis and the development of malignant tumors. Here, we designed short hairpin RNAs (shRNAs) to effectively knock down PER1 in SCC15 human oral squamous cell carcinoma cells. shRNA-mediated PER1 knockdown promoted SCC15 cell growth, proliferation, apoptosis resistance, migration and invasion in vitro . PER1 knockdown also increased the cells’ expression of KI-67, MDM2, BCL-2, MMP2 and MMP9 mRNA, and decreased expression of C-MYC, p53, BAX and TIMP-2 . In BALB/c nu/nu nude mice subcutaneously injected with SCC15 cells, PER1 knockdown in the cells enhanced tumor development, leading to increased tumor weights and volumes. These results suggest that PER1 is an important tumor suppressor gene and may be a useful molecular target for the treatment of cancer.

  • Aberrant expression of clock gene period1 and its correlations with the growth, proliferation and metastasis of buccal squamous cell carcinoma.
    PloS one, 2013
    Co-Authors: Ningbo Zhao, Kai Yang, Gen-ling Yang, Dan Chen, Hong Tang, Dan Zhao, Chunrong Zhao
    Abstract:

    Period1 (PER1) is an important core clock gene, which regulates normal cell proliferations and physiological rhythms of human beings. Recent studies have showed aberrant expressions and altered rhythms of PER1 were highly correlated to the carcinogenesis and development of malignant tumors. However, there is no study on the correlation of aberrant expressions and altered rhythms of PER1 with the growth, proliferation and metastasis of buccal squamous cell carcinoma (BSCC). In this study, PER1 and MMP-2 expression in the cancerous and adjacent noncancerous tissues of 38 patients with BSCC and its correlations with patients' clinical pathologic characteristics were investigated. A mouse model of BSCC was also established and mice were sacrificed at 4 different time points in a period of 24 hours. Xenografted tumor weight, proliferation index (PI), and mitotic index (MI) of tumors in the 4 time groups were detected. Results showed that PER1 expression was significantly down-regulated in cancerous tissues of patients with BSCC (P

  • Abnormal expression of PER1 circadian-clock gene in oral squamous cell carcinoma.
    OncoTargets and therapy, 2012
    Co-Authors: Rui Chen, Ningbo Zhao, Kai Yang, Dan Chen, Dan Zhao, Chunrong Zhao, Hong Tang
    Abstract:

    BACKGROUND The PER1 circadian-clock gene plays an important role in the regulation of many normal physiological rhythms in vivo. It has been revealed recently that abnormal expression of PER1 correlates closely with the occurrence and development of many cancers. However, the expression and significance of PER1 in oral squamous cell carcinoma (OSCC) remains unknown. The purpose of the present study was to investigate the direct links between aberrant PER1 expression and clinicopathological features of OSCC. METHODS PER1 expression in cancerous and adjacent noncancerous tissues from 41 patients with OSCC was detected by immunohistochemical staining and real-time reverse transcriptase polymerase chain reaction, and correlations were sought with clinicopathological features in patients. RESULTS Expression of PER1 mRNA and protein in OSCC was significantly reduced compared with that in adjacent noncancerous tissue (P 0.05). CONCLUSION Changes in PER1 expression may play an important role in the development, invasion, and metastasis of OSCC, and may also provide novel ideas and methods for investigation of the occurrence, development, and targeted treatment OSCC.

Jacob Richards - One of the best experts on this subject based on the ideXlab platform.

  • transcriptional regulation of nhe3 and sglt1 by the circadian clock protein PER1 in proximal tubule cells
    American Journal of Physiology-renal Physiology, 2015
    Co-Authors: Kristen Solocinski, Jacob Richards, Sean All, Kityan Cheng, Syed J Khundmiri, Michelle L Gumz
    Abstract:

    We have previously demonstrated that the circadian clock protein period (Per)1 coordinately regulates multiple genes involved in Na(+) reabsorption in renal collecting duct cells. Consistent with these results, PER1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. The proximal tubule is responsible for a majority of Na(+) reabsorption. Previous work has demonstrated that expression of Na(+)/H(+) exchanger 3 (NHE3) oscillates with a circadian pattern and Na(+)-glucose cotransporter (SGLT)1 has been demonstrated to be a circadian target in the colon, but whether these target genes are regulated by PER1 has not been investigated in the kidney. The goal of the present study was to determine if PER1 regulates the expression of NHE3, SGLT1, and SGLT2 in the kidney. Pharmacological blockade of nuclear PER1 entry resulted in decreased mRNA expression of SGLT1 and NHE3 but not SGLT2 in the renal cortex of mice. PER1 small interfering RNA and pharmacological blockade of PER1 nuclear entry in human proximal tubule HK-2 cells yielded the same results. Examination of heterogeneous nuclear RNA suggested that the effects of PER1 on NHE3 and SGLT1 expression occurred at the level of transcription. PER1 and the circadian protein CLOCK were detected at promoters of NHE3 and SGLT1. Importantly, both membrane and intracellular protein levels of NHE3 and SGLT1 were decreased after blockade of nuclear PER1 entry. This effect was associated with reduced activity of Na(+)-K(+)-ATPase. These data demonstrate a role for PER1 in the transcriptional regulation of NHE3 and SGLT1 in the kidney.

  • a role for the circadian clock protein PER1 in the regulation of the nacl co transporter ncc and the with no lysine kinase wnk cascade in mouse distal convoluted tubule cells
    Journal of Biological Chemistry, 2014
    Co-Authors: Jacob Richards, Robert S. Hoover, Sean All, Kityan Cheng, Michelle L Gumz
    Abstract:

    It has been well established that blood pressure and renal function undergo circadian fluctuations. We have demonstrated that the circadian protein PER1 regulates multiple genes involved in sodium transport in the collecting duct of the kidney. However, the role of PER1 in other parts of the nephron has not been investigated. The distal convoluted tubule (DCT) plays a critical role in renal sodium reabsorption. Sodium is reabsorbed in this segment through the actions of the NaCl co-transporter (NCC), which is regulated by the with-no-lysine kinases (WNKs). The goal of this study was to test if PER1 regulates sodium transport in the DCT through modulation of NCC and the WNK kinases, WNK1 and WNK4. Pharmacological blockade of nuclear PER1 entry resulted in decreased mRNA expression of NCC and WNK1 but increased expression of WNK4 in the renal cortex of mice. These findings were confirmed by using PER1 siRNA and pharmacological blockade of PER1 nuclear entry in mDCT15 cells, a model of the mouse distal convoluted tubule. Transcriptional regulation was demonstrated by changes in short lived heterogeneous nuclear RNA. Chromatin immunoprecipitation experiments demonstrated interaction of PER1 and CLOCK with the promoters of NCC, WNK1, and WNK4. This interaction was modulated by blockade of PER1 nuclear entry. Importantly, NCC protein expression and NCC activity, as measured by thiazide-sensitive, chloride-dependent 22Na uptake, were decreased upon pharmacological inhibition of PER1 nuclear entry. Taken together, these data demonstrate a role for PER1 in the transcriptional regulation of NCC, WNK1, and WNK4.

  • regulation of ncc and the wnk cascade by the circadian clock protein PER1 in murine distal convoluted tubule cells 1109 5
    The FASEB Journal, 2014
    Co-Authors: Jacob Richards, Robert S. Hoover, Sean All, Kityan Cheng, Michelle L Gumz
    Abstract:

    Blood pressure and renal function undergo circadian fluctuations. We have shown that the circadian protein PER1 regulates genes involved in sodium (Na) transport in the kidney collecting duct, but has not been investigated in other parts of the nephron. The distal convoluted tubule (DCT) plays a critical role in Na reabsorption in the nephron through the actions of the Na-Cl co-transporter (NCC), which is regulated by the with-no-lysine kinases (WNKs). Therefore, we wanted to test the hypothesis that PER1 regulates Na transport in the DCT through modulation of NCC, WNK1 and WNK4. Pharmacological blockade of nuclear PER1 entry resulted in decreased mRNA expression of NCC and WNK1, but increased expression of WNK4 in mouse renal cortex. These findings were confirmed by PER1 siRNA and pharmacological blockade of PER1 nuclear entry in mDCT15 cells, a model of the mouse distal convoluted tubule. Measurement of short-lived hnRNA demonstrated that the effect of PER1 was transcriptional. Chromatin immunoprecipita...

  • a role for the circadian clock protein PER1 in the regulation of aldosterone levels and renal na retention
    American Journal of Physiology-renal Physiology, 2013
    Co-Authors: Jacob Richards, Sean All, Kityan Cheng, George Skopis, Lauren A. Jeffers, Jeanette I Lynch, Charles S Wingo, Michelle L Gumz
    Abstract:

    The circadian clock plays an important role in the regulation of physiological processes, including renal function and blood pressure. We have previously shown that the circadian protein period (Per)1 regulates the expression of multiple Na+ transport genes in the collecting duct, including the α-subunit of the renal epithelial Na+ channel. Consistent with this finding, PER1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. We have also recently demonstrated the potential opposing actions of cryptochrome (Cry)2 on PER1 target genes. Recent work by others has demonstrated that Cry1/2 regulates aldosterone production through increased expression of the adrenal gland-specific rate-limiting enzyme 3β-dehydrogenase isomerase (3β-HSD). Therefore, we tested the hypothesis that PER1 plays a role in the regulation of aldosterone levels and renal Na+ retention. Using RNA silencing and pharmacological blockade of PER1 nuclear entry in the NCI-H295R human adrenal cell line, we showed that PER1 regulates 3β-HSD expression in vitro. These results were confirmed in vivo: mice with reduced levels of PER1 had decreased levels of plasma aldosterone and decreased mRNA expression of 3β-HSD. We postulated that mice with reduced PER1 would have a renal Na+-retaining defect. Indeed, metabolic cage experiments demonstrated that PER1 heterozygotes excreted more urinary Na+ compared with wild-type mice. Taken together, these data support the hypothesis that PER1 regulates aldosterone levels and that PER1 plays an integral role in the regulation of Na+ retention.

  • Role of PER1 and the mineralocorticoid receptor in the coordinate regulation of αENaC in renal cortical collecting duct cells.
    Frontiers in physiology, 2013
    Co-Authors: Jacob Richards, Sean All, Kityan Cheng, Lauren A. Jeffers, Michelle L Gumz
    Abstract:

    Renal function and blood pressure exhibit a circadian pattern of variation, but the molecular mechanism underlying this circadian regulation is not fully understood. We have previously shown that the circadian clock protein PER1 positively regulates the basal and aldosterone-mediated expression of the alpha subunit of the renal epithelial sodium channel (αENaC). The mechanism of this regulation has not been determined however. To further elucidate the mechanism of Mineralocorticoid Receptor (MR) and PER1 action, site-directed mutagenesis, DNA pull-down assays and chromatin immunoprecipitation methods were used to investigate the coordinate regulation of αENaC by PER1 and MR. Mutation of two circadian response E-boxes in the human αENaC promoter abolished both basal and aldosterone-mediated promoter activity. DNA pull down assays demonstrated the interaction of both MR and PER1 with the E-boxes from the αENaC promoter. These observations were corroborated by chromatin immunopreciptation experiments showing increased occupancy of MR and PER1 on an E-box of the αENaC promoter in the presence of aldosterone. This is the first report of an aldosterone-mediated increase in PER1 on a target gene promoter. Taken together, these results demonstrate the novel finding that PER1 and MR mediate the aldosterone response of αENaC through DNA/protein interaction in renal collecting duct cells.