The Experts below are selected from a list of 16875 Experts worldwide ranked by ideXlab platform
Qiyang He - One of the best experts on this subject based on the ideXlab platform.
-
protein kinase a and casein kinases mediate sequential phosphorylation events in the circadian Negative Feedback Loop
Genes & Development, 2007Co-Authors: Guocun Huang, Chengzu Long, Qiyang He, Shaojie Li, Lily Li, She ChenAbstract:Regulation of circadian clock components by phosphorylation plays essential roles in clock functions and is conserved from fungi to mammals. In the Neurospora circadian Negative Feedback Loop, FREQUENCY (FRQ) protein inhibits WHITE COLLAR (WC) complex activity by recruiting the casein kinases CKI and CKII to phosphorylate the WC proteins, resulting in the repression of frq transcription. On the other hand, CKI and CKII progressively phosphorylate FRQ to promote FRQ degradation, a process that is a major determinant of circadian period length. Here, by using whole-cell isotope labeling and quantitative mass spectrometry methods, we show that the WC-1 phosphorylation events critical for the Negative Feedback process occur sequentially-first by a priming kinase, then by the FRQ-recruited casein kinases. We further show that the cyclic AMP-dependent protein kinase A (PKA) is essential for clock function and inhibits WC activity by serving as a priming kinase for the casein kinases. In addition, PKA also regulates FRQ phosphorylation, but unlike CKI and CKII, PKA stabilizes FRQ, similar to the stabilization of human PERIOD2 (hPER2) due to the phosphorylation at the familial advanced sleep phase syndrome (FASPS) site. Thus, PKA is a key clock component that regulates several critical processes in the circadian Negative Feedback Loop.
-
light independent phosphorylation of white collar 1 regulates its function in the neurospora circadian Negative Feedback Loop
Journal of Biological Chemistry, 2005Co-Authors: Qiyang He, She Chen, Ping Cheng, Lixin WangAbstract:Abstract Phosphorylation is a major regulatory mechanism controlling circadian clocks. In the Neurospora circadian clock, the PER-ARNT-SIM (PAS) domain-containing transcription factor, WHITE COLLAR (WC)-1, acts both as the blue light photoreceptor of the clock and as a positive element in the circadian Negative Feedback Loop in constant darkness, by activating the transcription of the frequency (frq) gene. To understand the role of WC-1 phosphorylation, five in vivo WC-1 phosphorylation sites, located immediately downstream of the WC-1 zinc finger DNA binding domain, were identified by tandem mass spectrometry using biochemically purified endogenous WC-1 protein. Mutations of these phosphorylation sites suggest that they are major WC-1 phosphorylation sites under constant conditions but are not responsible for the light-induced hyperphosphorylation of WC-1. Although phosphorylation of these sites does not affect the light function of WC-1, strains carrying mutations of these sites show short period, low amplitude, or arrhythmic conidiation rhythms in constant darkness. Furthermore, normal or slightly higher levels of frq mRNA and FRQ proteins were observed in a mutant strain containing mutations of all five sites despite its low WC-1 levels. Together, these data suggest that phosphorylation of these sites Negatively regulates the function of WC-1 in the circadian Negative Feedback Loop and is important for the function of the Neurospora circadian clock.
-
regulation of the neurospora circadian clock by an rna helicase
Genes & Development, 2005Co-Authors: Ping Cheng, Qiyang He, Qun He, Lixin WangAbstract:Endogenous circadian (daily) clocks control a wide variety of physiological and molecular activities in most eukaryotic and some prokaryotic organisms. At the molecular level, autoregulatory Negative-Feedback Loops composed of positive and Negative elements form the core circadian oscillators (Dunlap 1999; King and Takahashi 2000; Reppert and Weaver 2001; Young and Kay 2001). The rhythmic activation of transcription of the Negative elements by the positive elements is thought to be the main basis for the generation of the endogenous rhythmicity. In the Neurospora frequency (frq)–white collar (wc)-based circadian Negative-Feedback Loop, a heterodimeric complex formed by WC-1 and WC-2 (two PAS domain-containing transcription factors) acts as the positive element and activates the transcription of frq by binding to its promoter (Crosthwaite et al. 1997; Cheng et al. 2001b; Loros and Dunlap 2001; Froehlich et al. 2003). FRQ proteins (large FRQ [lFRQ] and small FRQ [sFRQ] resulting from alternative translation initiation) form homodimeric complexes and function as the Negative elements in the Loop by repressing their own transcription (Aronson et al. 1994a; Garceau et al. 1997; Liu et al. 1997; Cheng et al. 2001a). To close the Negative-Feedback Loop, FRQ forms a complex with the WC proteins and prevents WC from binding to the frq promoter and activating frq transcription (Cheng et al. 2001a; Denault et al. 2001; Merrow et al. 2001; Froehlich et al. 2003). In strains lacking a functional FRQ protein, the Negative-Feedback Loop is impaired, resulting in high frq mRNA levels (Aronson et al. 1994a; Merrow et al. 1997; Yang et al. 2002). How FRQ inhibits the activity of WC complex is unclear. In frq null strains, in addition to their loss of circadian rhythmicities, less conidia and aerial hyphae are produced than a wild-type strain (Aronson et al. 1994b), suggesting that FRQ has functions outside the circadian Feedback Loops. In this study, we show that all FRQ proteins are in complex with FRH, a conserved RNA helicase. We demonstrate that FRH is an essential clock component in the Neurospora circadian Negative-Feedback Loop.
Mariamagdalena Georgescu - One of the best experts on this subject based on the ideXlab platform.
-
rip1 activates pi3k akt via a dual mechanism involving nf κb mediated inhibition of the mtor s6k irs1 Negative Feedback Loop and down regulation of pten
Cancer Research, 2009Co-Authors: Seongmi Park, Dawen Zhao, Kimmo J Hatanpaa, Bruce E Mickey, Debabrata Saha, David A Boothman, Michael D Story, Eric T Wong, Sandeep Burma, Mariamagdalena GeorgescuAbstract:Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a Negative Feedback Loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-kappaB (NF-kappaB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR Negative Feedback Loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 Negatively regulates mTOR transcription via a NF-kappaB-dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-kappaB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel Negative regulation of mTOR signaling at the transcriptional level by the NF-kappaB pathway. Our data suggest that the RIP1-NF-kappaB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis.
-
rip1 activates pi3k akt via a dual mechanism involving nf κb mediated inhibition of the mtor s6k irs1 Negative Feedback Loop and down regulation of pten
Cancer Research, 2009Co-Authors: Seongmi Park, Dawen Zhao, Kimmo J Hatanpaa, Bruce E Mickey, Debabrata Saha, David A Boothman, Michael D Story, Eric T Wong, Sandeep Burma, Mariamagdalena GeorgescuAbstract:Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a Negative Feedback Loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-κB (NF-κB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR Negative Feedback Loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 Negatively regulates mTOR transcription via a NF-κB–dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-κB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel Negative regulation of mTOR signaling at the transcriptional level by the NF-κB pathway. Our data suggest that the RIP1-NF-κB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis. [Cancer Res 2009;69(10):4107–11]
Seongmi Park - One of the best experts on this subject based on the ideXlab platform.
-
rip1 activates pi3k akt via a dual mechanism involving nf κb mediated inhibition of the mtor s6k irs1 Negative Feedback Loop and down regulation of pten
Cancer Research, 2009Co-Authors: Seongmi Park, Dawen Zhao, Kimmo J Hatanpaa, Bruce E Mickey, Debabrata Saha, David A Boothman, Michael D Story, Eric T Wong, Sandeep Burma, Mariamagdalena GeorgescuAbstract:Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a Negative Feedback Loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-kappaB (NF-kappaB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR Negative Feedback Loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 Negatively regulates mTOR transcription via a NF-kappaB-dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-kappaB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel Negative regulation of mTOR signaling at the transcriptional level by the NF-kappaB pathway. Our data suggest that the RIP1-NF-kappaB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis.
-
rip1 activates pi3k akt via a dual mechanism involving nf κb mediated inhibition of the mtor s6k irs1 Negative Feedback Loop and down regulation of pten
Cancer Research, 2009Co-Authors: Seongmi Park, Dawen Zhao, Kimmo J Hatanpaa, Bruce E Mickey, Debabrata Saha, David A Boothman, Michael D Story, Eric T Wong, Sandeep Burma, Mariamagdalena GeorgescuAbstract:Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a Negative Feedback Loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-κB (NF-κB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR Negative Feedback Loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 Negatively regulates mTOR transcription via a NF-κB–dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-κB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel Negative regulation of mTOR signaling at the transcriptional level by the NF-κB pathway. Our data suggest that the RIP1-NF-κB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis. [Cancer Res 2009;69(10):4107–11]
Vivek Kumar - One of the best experts on this subject based on the ideXlab platform.
-
rhythmic per abundance defines a critical nodal point for Negative Feedback within the circadian clock mechanism
Molecular Cell, 2009Co-Authors: Rongmin Chen, Aaron Schirmer, Yongjin Lee, Hyeongmin Lee, Vivek Kumar, Seung Hee YooAbstract:Circadian rhythms in mammals are generated by a transcriptional Negative Feedback Loop that is driven primarily by oscillations of PER and CRY, which inhibit their own transcriptional activators, CLOCK and BMAL1. Current models posit that CRY is the dominant repressor, while PER may play an accessory role. In this study, however, constitutive expression of PER, and not CRY1, severely disrupted the clock in fibroblasts and liver. Furthermore, constitutive expression of PER2 in the brain and SCN of transgenic mice caused a complete loss of behavioral circadian rhythms in a conditional and reversible manner. These results demonstrate that rhythmic levels of PER2, rather than CRY1, are critical for circadian oscillations in cells and in the intact organism. Our biochemical evidence supports an elegant mechanism for the disparity: PER2 directly and rhythmically binds to CLOCK:BMAL1, while CRY only interacts indirectly; PER2 bridges CRY and CLOCK:BMAL1 to drive the circadian Negative Feedback Loop.
-
rhythmic per abundance defines a critical nodal point for Negative Feedback within the circadian clock mechanism
Molecular Cell, 2009Co-Authors: Rongmin Chen, Aaron Schirmer, Vivek Kumar, Joseph S TakahashiAbstract:Circadian rhythms in mammals are generated by a transcriptional Negative Feedback Loop that is driven primarily by oscillations of PER and CRY, which inhibit their own transcriptional activators, CLOCK and BMAL1. Current models posit that CRY is the dominant repressor, while PER may play an accessory role. In this study, however, constitutive expression of PER, and not CRY1, severely disrupted the clock in fibroblasts and liver. Furthermore, constitutive expression of PER2 in the brain and SCN of transgenic mice caused a complete loss of behavioral circadian rhythms in a conditional and reversible manner. These results demonstrate that rhythmic levels of PER2, rather than CRY1, are critical for circadian oscillations in cells and in the intact organism. Our biochemical evidence supports an elegant mechanism for the disparity: PER2 directly and rhythmically binds to CLOCK:BMAL1, while CRY only interacts indirectly; PER2 bridges CRY and CLOCK:BMAL1 to drive the circadian Negative Feedback Loop.
Shuxu Zhang - One of the best experts on this subject based on the ideXlab platform.
-
disturbance of the let 7 lin28 double Negative Feedback Loop is associated with radio and chemo resistance in non small cell lung cancer
PLOS ONE, 2017Co-Authors: Jun Yin, Jian Zhao, Guangping Yang, Ruihao Wang, Linjing Wang, Guoqian Zhang, Lu Dai, Boyu Liao, Shuxu ZhangAbstract:Radio- and chemo-resistance represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC) and the underlying molecular mechanisms are not known. In the present study, during induction of radio- or chemo-resistance in NSCLC cells, dynamic analyses revealed that decreased expression of let-7 induced by irradiation or cisplatin resulted in increased expression of its target gene LIN28, and increased expression of LIN28 then contributed to further decreased expression of let-7 by inhibiting its maturation and biogenesis. Moreover, we showed that down-regulation of let-7 and up-regulation of LIN28 expression promoted resistance to irradiation or cisplatin by regulating the single-cell proliferative capability of NSCLC cells. Consequently, in NSCLC cells, let-7 and LIN28 can form a double-Negative Feedback Loop through mutual inhibition, and disturbance of the let-7/LIN28 double-Negative Feedback Loop induced by irradiation or chemotherapeutic drugs can result in radio- and chemo-resistance. In addition, low expression of let-7 and high expression of LIN28 in NSCLC patients was associated significantly with resistance to radiotherapy or chemotherapy. Therefore, our study demonstrated that disturbance of the let-7/LIN28 double-Negative Feedback Loop is involved in the regulation of radio- and chemo-resistance, and that let-7 and LIN28 could be employed as predictive biomarkers of response to radiotherapy or chemotherapy in NSCLC patients.
