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Nancy H Colburn - One of the best experts on this subject based on the ideXlab platform.

  • PDCD4 regulates axonal growth by translational repression of neurite growth related genes and is modulated during nerve injury responses
    RNA, 2020
    Co-Authors: Andres Di Paolo, Nancy H Colburn, Guillermo Eastman, Raquel Mesquitaribeiro, Joaquina Farias, Andrew Macklin, Thomas Kislinger, David J Munroe, Jose Roberto Sotelo Sosa
    Abstract:

    Programmed cell death 4 (PDCD4) protein is a tumor suppressor that inhibits translation through the mTOR-dependent initiation factor EIF4A, but its functional role and mRNA targets in neurons remain largely unknown. Our work identified that PDCD4 is highly expressed in axons and dendrites of CNS and PNS neurons. Using loss- and gain-of-function experiments in cortical and dorsal root ganglia primary neurons, we demonstrated the capacity of PDCD4 to negatively control axonal growth. To explore PDCD4 transcriptome and translatome targets, we used Ribo-seq and uncovered a list of potential targets with known functions as axon/neurite outgrowth regulators. In addition, we observed that PDCD4 can be locally synthesized in adult axons in vivo, and its levels decrease at the site of peripheral nerve injury and before nerve regeneration. Overall, our findings demonstrate that PDCD4 can act as a new regulator of axonal growth via the selective control of translation, providing a target mechanism for axon regeneration and neuronal plasticity processes in neurons.

  • tumor suppressor PDCD4 attenuates sin1 translation to inhibit invasion in colon carcinoma
    Oncogene, 2017
    Co-Authors: Qing Wang, Alyson R Baker, Nancy H Colburn, Jiang Zhu, Yawen Wang, Yong Dai, Yanlei Wang, Chi Wang, Jinpeng Liu, Hsinsheng Yang
    Abstract:

    Programmed cell death 4 (PDCD4), a tumor invasion suppressor, is frequently downregulated in colorectal cancer and other cancers. In this study, we find that loss of PDCD4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that PDCD4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how PDCD4 regulates Sin1 translation, the SIN1 5' untranslated region (5'UTR) was fused with luciferase reporter and named as 5'Sin1-Luc. PDCD4 knockdown/knockout significantly increased the translation of 5'Sin1-Luc but not the control luciferase without the SIN1 5'UTR, suggesting that Sin1 5'UTR is necessary for PDCD4 to inhibit Sin1 translation. Ectopic expression of wild-type PDCD4 and PDCD4(157-469), a deletion mutant that binds to translation initiation factor 4A (eIF4A), sufficiently inhibited Sin1 translation, and thus suppressed mTORC2 kinase activity and invasion in colon tumor cells. By contrast, PDCD4(157-469)(D253A,D418A), a mutant that does not bind to eIF4A, failed to inhibit Sin1 translation, and consequently failed to repress mTORC2 activity and invasion. In addition, directly inhibiting eIF4A with silvestrol significantly suppressed Sin1 translation and attenuated invasion. These results indicate that PDCD4-inhibited Sin1 translation is through suppressing eIF4A, and functionally important for suppression of mTORC2 activity and invasion. Moreover, in colorectal cancer tissues, the Sin1 protein but not mRNA was significantly upregulated while PDCD4 protein was downregulated, suggesting that loss of PDCD4 might correlate with Sin1 protein level but not mRNA level in colorectal cancer patients. Taken together, our work reveals a novel mechanism by which PDCD4 inhibits Sin1 translation to attenuatemTORC2 activity and thereby suppresses invasion.

  • inflammation induced loss of PDCD4 is mediated by phosphorylation dependent degradation
    Carcinogenesis, 2011
    Co-Authors: Tobias Schmid, Alyson R Baker, Magdalena M Bajer, Johanna S Blees, Lisa K Eifler, Larissa Milke, Daniela Rubsamen, Kathrin Schulz, Andreas Weigert, Nancy H Colburn
    Abstract:

    The tumor suppressor programmed cell death 4 (PDCD4) is lost in various tumor tissues. Loss of PDCD4 has been associated with increased tumorigenic potential and tumor progression. While various mechanisms of PDCD4 regulation have been described, the effect of an inflammatory tumor microenvironment on PDCD4 protein expression has not been characterized so far. In the present study, we aimed to elucidate the molecular mechanisms of PDCD4 protein regulation in tumor cells under inflammatory conditions. 12-O-tetradecanoylphorbol 13-acetate-induced differentiation of human U937 monocytes increased the expression and secretion of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-6 and IL-8. Exposure to conditioned medium (CM) of these activated macrophages markedly decreased PDCD4 protein expression in various tumor cells. Similarly, indirect coculture with such activated U937 monocyte-derived macrophages resulted in the loss of PDCD4 protein in tumor cells. Decreased PDCD4 protein levels were attributable to enhanced proteasomal degradation, diminishing PDCD4 protein half-life. Proteasomal degradation required activation of phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling. Since macrophage-CM sufficed to induce PDCD4 degradation, PDCD4 downregulation was determined to be an indirect unidirectional effect of the macrophages on the tumor cells. PDCD4 protein expression was also attenuated in vivo in mouse colon tissue in response to dextran sodium sulfate-induced colitis. In summary, we characterized PI3K-mTOR-dependent proteasome-mediated PDCD4 degradation in tumor cells in the inflammatory tumor microenvironment. Consequently, stabilization of PDCD4 protein could provide a promising novel avenue for therapeutics targeting inflammation-associated tumors.

  • downregulation of PDCD4 by mir 21 facilitates glioblastoma proliferation in vivo
    Neuro-oncology, 2011
    Co-Authors: Arti B Gaur, Nancy H Colburn, Susan L Holbeck, Mark A Israel
    Abstract:

    MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in developmental and physiological processes and are implicated in the pathogenesis of several human diseases, including cancer. They function by regulating target gene expression post-transcriptionally. In this study, we examined the role of oncogenic mir-21 in the pathogenesis of glioblastoma, the most aggressive form of primary brain tumor. We have previously reported that mir-21 is expressed at higher levels in primary glioblastoma-tissue and glioblastoma-derived cell lines than in normal brain tissue. We demonstrate that downregulation of mir-21 in glioblastoma-derived cell lines results in increased expression of its target, programmed cell death 4 (PDCD4), a known tumor-suppressor gene. In addition, our data indicate that either downregulation of mir-21 or overexpression of its target, PDCD4, in glioblastoma-derived cell lines leads to decreased proliferation, increased apoptosis, and decreased colony formation in soft agar. Using a glioblastoma xenograft model in immune-deficient nude mice, we observe that glioblastomaderived cell lines in which mir-21 levels are downregulated or PDCD4 is over-expressed exhibit decreased tumor formation and growth. Significantly, tumors grow when the glioblastoma-derived cell lines are transfected with anti-mir-21 and siRNA to PDCD4, confirming that the tumor growth is specifically regulated by PDCD4. These critical in vivo findings demonstrate an important functional linkage between mir-21 and PDCD4 and further elucidate the molecular mechanisms by which the known high level of mir-21 expression in glioblastoma can attribute to tumorigenesis—namely, inhibition of PDCD4 and its tumor-suppressive functions.

  • PDCD4 repression of lysyl oxidase inhibits hypoxia induced breast cancer cell invasion
    Oncogene, 2010
    Co-Authors: A N Santhanam, Alyson R Baker, Glenn Hegamyer, D A Kirschmann, Nancy H Colburn
    Abstract:

    Metastasis to bone, liver and lungs is the primary cause of death in breast cancer patients. Our studies have revealed that the novel tumor suppressor PDCD4 inhibits breast cancer cell migration and invasion in vitro. Loss of PDCD4 in human nonmetastatic breast cancer cells increased the expression of lysyl oxidase (LOX) mRNA. LOX is a hypoxia-inducible amine oxidase, the activity of which enhances breast cancer cell invasion in vitro and in vivo. Specific inhibition of LOX activity by β-aminopropionitrile or small interfering RNA decreased the invasiveness of T47D and MCF7 breast cancer cells attenuated for PDCD4 function. Most significantly, loss of PDCD4 augments hypoxia induction of LOX as well. Conversely, overexpression of PDCD4 significantly reversed the hypoxia induction of LOX expression in T47D cells attenuated for PDCD4. However, PDCD4 did not affect hypoxia-inducible factor-1 (HIF-1) protein expression or HIF-1-responsive element-luciferase activity in response to hypoxia, suggesting that PDCD4 regulation of LOX occurs through an HIF-independent mechanism. Nevertheless, the loss of PDCD4 early in cancer progression may have an important role in the increased sensitivity of cancer cells to hypoxia through increased LOX activity and concomitant enhanced invasiveness.

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

  • the role of PDCD4 in tumour suppression and protein translation
    Biology of the Cell, 2018
    Co-Authors: Qing Wang, Hsinsheng Yang
    Abstract:

    Programmed cell death 4 (PDCD4), a tumour suppressor, is frequently down-regulated in various types of cancer. PDCD4 has been demonstrated to efficiently suppress tumour promotion, progression and proliferation. The biochemical function of PDCD4 is a protein translation inhibitor. Although the fact that PDCD4 inhibits protein translation has been known for more than a decade, the mechanism by which PDCD4 controls tumorigenesis through translational regulation of its target genes is still not fully understood. Recent studies show that PDCD4 inhibits translation of stress-activated-protein kinase interacting protein 1 to suppress tumour invasion, depicting a picture of how PDCD4 inhibits tumorigenesis through translational inhibition. Thus, understanding the mechanism of how PDCD4 attenuates tumorigenesis by translational control should provide a new strategy for combating cancer.

  • tumor suppressor PDCD4 attenuates sin1 translation to inhibit invasion in colon carcinoma
    Oncogene, 2017
    Co-Authors: Qing Wang, Alyson R Baker, Nancy H Colburn, Jiang Zhu, Yawen Wang, Yong Dai, Yanlei Wang, Chi Wang, Jinpeng Liu, Hsinsheng Yang
    Abstract:

    Programmed cell death 4 (PDCD4), a tumor invasion suppressor, is frequently downregulated in colorectal cancer and other cancers. In this study, we find that loss of PDCD4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that PDCD4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how PDCD4 regulates Sin1 translation, the SIN1 5' untranslated region (5'UTR) was fused with luciferase reporter and named as 5'Sin1-Luc. PDCD4 knockdown/knockout significantly increased the translation of 5'Sin1-Luc but not the control luciferase without the SIN1 5'UTR, suggesting that Sin1 5'UTR is necessary for PDCD4 to inhibit Sin1 translation. Ectopic expression of wild-type PDCD4 and PDCD4(157-469), a deletion mutant that binds to translation initiation factor 4A (eIF4A), sufficiently inhibited Sin1 translation, and thus suppressed mTORC2 kinase activity and invasion in colon tumor cells. By contrast, PDCD4(157-469)(D253A,D418A), a mutant that does not bind to eIF4A, failed to inhibit Sin1 translation, and consequently failed to repress mTORC2 activity and invasion. In addition, directly inhibiting eIF4A with silvestrol significantly suppressed Sin1 translation and attenuated invasion. These results indicate that PDCD4-inhibited Sin1 translation is through suppressing eIF4A, and functionally important for suppression of mTORC2 activity and invasion. Moreover, in colorectal cancer tissues, the Sin1 protein but not mRNA was significantly upregulated while PDCD4 protein was downregulated, suggesting that loss of PDCD4 might correlate with Sin1 protein level but not mRNA level in colorectal cancer patients. Taken together, our work reveals a novel mechanism by which PDCD4 inhibits Sin1 translation to attenuatemTORC2 activity and thereby suppresses invasion.

  • decreased level of PDCD4 programmed cell death 4 protein activated cell proliferation in the lung of a j mouse
    Journal of Aerosol Medicine and Pulmonary Drug Delivery, 2010
    Co-Authors: Soonkyung Hwang, Arash Minaitehrani, Hwangtae Lim, Jiyoung Shin, Keeho Lee, Keerang Park, Yeonsoo Kim, George R Beck, Hsinsheng Yang, Myunghaing Cho
    Abstract:

    Abstract Background: Programmed cell death 4 (PDCD4), a protein that binds to eukaryotic initiation factor 4A (eIF4A), inhibits the initiation of translation. Although a number of tumor suppressors target transcription, PDCD4 is the first suppressor targeting protein translation, and has also been suggested to function as a tumor suppressor gene in human cancer. The majority of tumor suppressors are mutationally inactivated, but the expression of PDCD4 is downregulated with progression in a number of human cancer sites, including the lung. Methods: An aerosol of lentivirus-shRNA PDCD4 was delivered into A/J mice, through a nose-only inhalation system twice a week for 1 month. Results and Conclusions: Downregulated PDCD4 resulted in increase levels of antiapoptotic and uPA-regulated proteins. We also found that downregulated PDCD4 induced the mTOR/p70S6K pathway and cell-cycle proteins. Our results suggest that PDCD4 may perform a critical function in the regulation of lung cancer cell proliferation.

  • downregulation of e cadherin is an essential event in activating β catenin tcf dependent transcription and expression of its target genes in PDCD4 knockdown cells
    Oncogene, 2010
    Co-Authors: Qing Wang, Heike Allgayer, Zhenxiao Sun, Hsinsheng Yang
    Abstract:

    We reported earlier that knockdown of tumor suppressor PDCD4 (programed cell death 4) downregulates E-cadherin expression and activates beta-catenin/Tcf (T-cell factor)-dependent transcription in colon tumor cells. However, the underlying mechanism of these observations remains unknown. In this study, we showed that knockdown of PDCD4 downregulates E-cadherin expression through elevated protein level of Snail. Over-expression of PDCD4 upregulates E-cadherin expression and inhibits beta-catenin/Tcf-dependent transcription. We then showed that knockdown of E-cadherin activates beta-catenin/Tcf-dependent transcription. Conversely, over-expression of E-cadherin in PDCD4 knockdown cells inhibits beta-catenin/Tcf-dependent transcription. In addition, PDCD4 knockdown stimulates urokinase-type plasminogen activator receptor (u-PAR) and c-Myc expression, whereas u-PAR and c-Myc expression can be reversed by over-expressing E-cadherin in PDCD4 knockdown cells. Using chromatin immunoprecipitation, we showed that beta-catenin/Tcf4 directly binds to the promoters of u-PAR and c-myc in PDCD4 knockdown cells. Futhermore, knockdown of u-PAR or c-Myc inhibits invasion in PDCD4 knockdown cells, suggesting that both u-PAR and c-Myc contribute to invasion induced by PDCD4 knockdown. Taken together, our data showed that elevated Snail expression by PDCD4 knockdown leads to downregulation of E-cadherin resulting in activating beta-catenin/Tcf-dependent transcription and stimulating the expression of c-Myc and u-PAR, thus providing molecular explanation of how PDCD4 suppresses tumor invasion.

  • structural basis for translational inhibition by the tumour suppressor PDCD4
    The EMBO Journal, 2009
    Co-Authors: Hsinsheng Yang, Qing Wang, Portia G Loh, M A Walsh, Xiaoxing Wang, Zhihong Cheng, Ding Xiang Liu, Haiwei Song
    Abstract:

    PDCD4 is a tumour suppressor protein. It inhibits translation through interaction with translation initiator eIF4A, resulting in the suppression of neoplastic transformation and tumour invasion. Here, we present the crystal structures of an N-terminal-truncated PDCD4 in free form and in complex with eIF4A. Upon binding to eIF4A, PDCD4 undergoes a marked conformational change to form a heterotrimeric complex with eIF4A, with one PDCD4 binding to two eIF4A molecules in two different modes. The binding of PDCD4 to eIF4A is required to inhibit the enzymatic activity of eIF4A, translation initiation, and AP-1-dependent transcription. Both MA3 domains are required to efficiently compete with the C-terminal domain of eIF4G (eIF4Gc) for binding to eIF4A whereas a single MA3 is sufficient to inhibit translation. Our structural and mutational analyses reveal that PDCD4 inhibits translation initiation by trapping eIF4A in an inactive conformation, and blocking its incorporation into the eIF4F complex.

Karl-heinz Klempnauer - One of the best experts on this subject based on the ideXlab platform.

  • PDCD4 controls the g1 s phase transition in a telomerase immortalized epithelial cell line and affects the expression level and translation of multiple mrnas
    Scientific Reports, 2020
    Co-Authors: Astrid Haas, Benedikt S Nilges, Sebastian A Leidel, Karl-heinz Klempnauer
    Abstract:

    : PDCD4, the protein encoded by the tumor suppressor gene PDCD4 (programmed cell death 4) has been implicated in the control of cellular transcription and translation by modulating the activity of specific transcription factors and suppressing the translation of mRNAs with structured 5'-UTRs. Most studies of human PDCD4 have employed tumor cell lines, possibly resulting in a biased picture of its role in normal cells. Here, we have studied the function of PDCD4 in a telomerase-immortalized human epithelial cell line. We show for the first time that PDCD4 is required for the G1/S-transition, demonstrating its crucial role in the cell cycle. Inhibition of p53-dependent activation of p21WAF1/CIP1 overrides the requirement for PDCD4 for the G1/S-transition, suggesting that PDCD4 counteracts basal p53 activity to prevent activation of the G1/S checkpoint by p53. Transcriptome and ribosome profiling data show that silencing of PDCD4 changes the expression levels and translation of many mRNAs, providing an unbiased view of the cellular processes that are affected by PDCD4 in an epithelial cell line. Our data identify PDCD4 as a key regulator of cell cycle- and DNA-related functions that are inhibited when it is silenced, suggesting that decreased expression of PDCD4 might contribute to tumor development by compromising genomic integrity.

  • abstract 3190 inhibition of the translation of a myb mrna by tumor suppressor protein PDCD4
    Cancer Research, 2013
    Co-Authors: A Biyanee, Karl-heinz Klempnauer
    Abstract:

    PDCD4 (Programmed cell death protein 4) was first identified as a protein to be expressed during apoptosis. Later it was shown that PDCD4 acts as a tumor suppressor protein and regulates the cellular processes on various levels, encompassing transcription and translation. PDCD4 interacts with the translation initiation factor eIF4A and inhibits its helicase activity which is required to unwind secondary structures in the 5’UTRs of mRNAs. Previous studies on artificial mRNAs have revealed that it inhibits the translation of mRNAs with secondary structures in their 5’ UTRs. Recently, c-myb mRNA was identified as a natural target RNA of PDCD4. A-myb is a member of the myb family which is expressed in certain hematopoietic cells, such as B-cells, but also in certain non-hematopoietic cells. We have observed that PDCD4 inhibits the translation of A-myb mRNA in co-transfection experiments using PDCD4 expression vectors as well as on the endogenous level, as demonstrated by the analysis of a PDCD4 knock-out model in the Chicken B-cell line DT40. We found that a mutant of PDCD4 which no longer interacts with eIF4 is still able to inbihit the translation of A-myb RNA, suggesting that PDCD4 acts in an eIF4A independent manner and contradicting the current view of how PDCD4 suppresses translation. Similar to the situation in the case of c-myb RNA we have localized the PDCD4 responsive region in the coding region of A-myb mRNA. We therefore conclude that PDCD4 suppresses the translation of A-myb RNA by a novel mechanism. Ribosome density profiling technique is widely used nowadays to explore the topography of the various stages of translation. Currently we aim to exploit the technique of ribosome density profiling to further understand how PDCD4 affects the translation of A-myb RNA. Citation Format: Abhiruchi Biyanee, Karl-Heinz Klempnauer. Inhibition of the translation of A-myb mRNA by tumor suppressor protein PDCD4. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3190. doi:10.1158/1538-7445.AM2013-3190

  • Tumor suppressor protein PDCD4 inhibits translation of p53 mRNA.
    The Journal of biological chemistry, 2011
    Co-Authors: Lena Wedeken, Priyanka Singh, Karl-heinz Klempnauer
    Abstract:

    The tumor suppressor protein PDCD4 is thought to suppress translation of mRNAs containing structured 5′-UTRs by interacting with translation initiation factor eIF4A and inhibiting its helicase activity. However, natural target mRNAs regulated by PDCD4 so far are mostly unknown. Here, we identified p53 mRNA as a translational target of PDCD4. We found that PDCD4 is associated with p53 mRNA and suppresses its translation. The inhibitory effect of PDCD4 on the translation of p53 mRNA depends on the ability of PDCD4 to interact with eIF4A and is mediated by the 5′-UTR of p53 mRNA, which is able to form a stable stem-loop structure. We show that treatment of cells with DNA-damaging agents decreases the expression of PDCD4. This suggests that translational suppression by PDCD4 plays a role in maintaining a low level of p53 in unstressed cells and that this suppression is abrogated due to low levels of PDCD4 after DNA damage. Overall, our work demonstrates for the first time that PDCD4 is directly involved in translational suppression of a natural mRNA with a 5′-structured UTR and provides novel insight into the translational control of p53 expression.

  • sirna mediated knockdown of PDCD4 expression causes upregulation of p21 waf1 cip1 expression
    Oncogene, 2008
    Co-Authors: Nadja Bitomsky, N Wethkamp, R Marikkannu, Karl-heinz Klempnauer
    Abstract:

    The transformation suppressor gene, programmed cell death gene 4 (PDCD4), inhibits tumor-promoter-mediated transformation of mouse keratinocytes and has been implicated as a tumor suppressor gene in the development of human cancer. The PDCD4 protein interacts with translation initiation factors eIF4A and eIF4G and binds to RNA, suggesting that it might be involved in regulating protein translation or other aspects of RNA metabolism. To study the function of PDCD4 in more detail, we have downregulated PDCD4 expression in HeLa cells by stable expression of shRNA. We have found that diminished PDCD4 expression leads to increased expression of p21(Waf1/Cip1) and several other p53-regulated genes. Reporter gene studies demonstrate that PDCD4 interferes with the activation of p53-responsive promoters genes by p53. PDCD4 knockdown cells show decreased apoptosis and increased survival after UV irradiation. Taken together, our observations suggest a model in which low PDCD4 expression after DNA damage favors the survival of cells, which would be eliminated by apoptosis under normal levels of PDCD4 expression. Our results provide the first evidence that PDCD4 is important role in the DNA-damage response and suggest that low levels of PDCD4 expression observed in certain tumor cells contribute to tumorigenesis by affecting the fate of DNA-damaged cells.

  • transformation suppressor protein PDCD4 interferes with jnk mediated phosphorylation of c jun and recruitment of the coactivator p300 by c jun
    Oncogene, 2004
    Co-Authors: Nadja Bitomsky, Maret Bohm, Karl-heinz Klempnauer
    Abstract:

    The transformation suppressor gene PDCD4 (programmed cell death gene 4) inhibits the tumor-promoter mediated transformation of mouse keratinocytes and has recently been implicated as a potential tumor suppressor gene in the development of human lung cancer. Biochemical analysis has suggested that the PDCD4 protein is involved in protein translation as well as in nuclear events. Recent work has shown that PDCD4 suppresses the transactivation of AP-1 responsive promoters by c-Jun, suggesting that the transformation-suppressor activity of PDCD4 might be due, at least in part, to the inhibition of c-Jun activity. Here, we have addressed how PDCD4 inhibits c-Jun. We show that PDCD4 interferes with the phosphorylation of c-Jun by Jun N-terminal kinase (JNK). The inhibition of c-Jun phosphorylation by PDCD4 appears not to be due to a general suppression of JNK activity, our data rather suggest that PDCD4 interacts with c-Jun and thereby blocks phosphorylation of c-Jun. In addition to affecting c-Jun phosphorylation, PDCD4 blocks the recruitment of the coactivator p300 by c-Jun. Taken together, our results strongly suggest that PDCD4 is directly involved in the regulation of c-Jun activity.

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

  • tumor suppressor gene PDCD4 negatively regulates autophagy by inhibiting the expression of autophagy related gene atg5
    Autophagy, 2013
    Co-Authors: Xingguo Song, Youhai H Chen, Xia Zhang, Xiaoyan Wang, Faliang Zhu, Chun Guo, Qun Wang, Yongyu Shi, Jianing Wang, Lining Zhang
    Abstract:

    PDCD4 (programmed cell death protein 4), a suppressor of gene transcription and translation, plays a crucial inhibitory role in several types of human tumors. However, its underlying mechanisms remain unclear. Autophagy, an evolutionarily conserved catabolic process, maintains cellular homeostasis under stress conditions such as starvation and plays a crucial role in tumor initiation and progression. We report here that PDCD4 inhibits autophagy in multiple cell types both in vitro and in vivo, which in turn contributes to its tumor suppressor activity. Importantly, PDCD4 inhibits the expression of an essential autophagy related gene, ATG5 and the formation of an ATG12–ATG5 complex, and its ma3 domains are required for PDCD4-mediated inhibition of autophagy. Unlike most tumor suppressors that act as positive or dual regulators of autophagy, our findings indicate that PDCD4 negatively regulates autophagy by targeting ATG5, which provides a novel mechanism of tumor suppression.

  • the microrna 21 PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Qingguo Ruan, Derek S Johnson, Ting Wang, Vasumathi Kameswaran, Qin Wei, Franz M Matschinsky, Weiyun Shi, Youhai H Chen
    Abstract:

    Death of pancreatic β cells is a pathological hallmark of type 1 diabetes (T1D). However, the molecular mechanisms of β cell death and its regulation are poorly understood. Here we describe a unique regulatory pathway of β cell death that comprises microRNA-21, its target tumor suppressor PDCD4, and its upstream transcriptional activator nuclear factor-κB (NF-κB). In pancreatic β cells, c-Rel and p65 of the NF-κB family activated the mir21 gene promoter and increased miR-21 RNA levels; miR-21 in turn decreased the level of PDCD4, which is able to induce cell death through the Bax family of apoptotic proteins. Consequently, PDCD4 deficiency in pancreatic β cells renders them resistant to death, and PDCD4 deficiency in NOD or C57BL/6 mice conferred resistance to spontaneous diabetes and diabetes induced by autoimmune T cells or the β cell toxin streptozotocin (STZ). Thus, the NF-κB-microRNA-21-PDCD4 axis plays a crucial role in T1D and represents a unique therapeutic target for treating the disease.

  • programmed cell death 4 enhances chemosensitivity of ovarian cancer cells by activating death receptor pathway in vitro and in vivo
    Cancer Science, 2010
    Co-Authors: Xia Zhang, Youhai H Chen, Xingguo Song, Xiaoyan Wang, Yongyu Shi, Olubunmi Afonja, Chunmei Liu, Yukun Wang, Lining Zhang
    Abstract:

    Chemoresistance is a major cause of treatment failure in ovarian cancer. Therefore, it is necessary to explore alternative therapeutic methods to overcome drug resistance for ovarian cancer treatment. We previously reported that programmed cell death 4 (PDCD4), a tumor suppressor, significantly suppresses the malignant phenotype of ovarian cancer cells and its lost or low expression in ovarian cancer is associated with unfavorable prognosis of patients. Here we show that PDCD4 improves the sensitivity of ovarian cancer cells to platinum-based chemotherapy. Overexpression of PDCD4 enhanced chemosensitivity in SKOV3 and CAOV3 cells with low levels of PDCD4, whereas knockdown of PDCD4 reduced chemosensitivity in OVCAR3 cells with high levels of PDCD4. Subsequently, the combination of enforced PDCD4 expression with cisplatin treatment significantly suppressed ovarian tumor growth in a xenograft animal model. The PDCD4 effect appears to be specific for cisplatin and carboplatin, not affecting cyclophosphamide, etoposide, or paclitaxel. Mechanistically, PDCD4 significantly increased cisplatin-induced cleavage of caspase-3 and caspase-8, but had only a slight impact on caspase-9 cleavage and the expression of Bax and Bcl-2 in vitro and in vivo. A specific caspase-8 inhibitor, Z-ITED-FMK, attenuated cisplatin-induced apoptosis in PDCD4-overexpressing ovarian cancer cells. Taken together, our results indicate that PDCD4 enhances cisplatin-induced apoptosis by mainly activating the death receptor pathway, and PDCD4 gene transfer in combination with cisplatin therapy may break the resistance of ovarian cancer cells to chemotherapy.

  • negative regulation of tlr4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microrna mir 21
    Nature Immunology, 2010
    Co-Authors: Frederick J Sheedy, Youhai H Chen, Eva M Palssonmcdermott, Elizabeth J Hennessy, Cara Martin, John J Oleary, Qingguo Ruan, Derek S Johnson, Luke A J Oneill
    Abstract:

    The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-kappaB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-kappaB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-kappaB. Transfection of cells with a miR-21 precursor blocked NF-kappaB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in PDCD4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation.

  • PDCD4 gene silencing in gliomas is associated with 5 cpg island methylation and unfavourable prognosis
    Journal of Cellular and Molecular Medicine, 2009
    Co-Authors: Fei Gao, Xia Zhang, Xiaoyan Wang, Faliang Zhu, Chun Guo, Qun Wang, Wensheng Sun, Chengjun Zhou, Yun Zhang, Youhai H Chen
    Abstract:

    Programmed cell death 4 (PDCD4) is a newly described tumour suppressor that inhibits oncogenesis by suppressing gene transcription and translation. Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas. However, the molecular mechanisms responsible for PDCD4 gene silencing in tumour cells remain unclear. Here we report the identification of 5′CpG island methylation as the predominant cause of PDCD4 mRNA silencing in gliomas. The methylation of the PDCD4 5′CpG island was found in 47% (14/30) of glioma tissues, which was significantly associated with the loss of PDCD4 mRNA expression (γ=−1.000, P < 0.0001). Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity. Longitudinal studies of a cohort of 84 patients with gliomas revealed that poor prognosis of patients with high-grade tumours were significantly associated with loss of PDCD4 expression. Thus, our current study suggests, for the first time, that PDCD4 5′CpG island methylation blocks PDCD4 expression at mRNA levels in gliomas. These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.

Anita H. Corbett - One of the best experts on this subject based on the ideXlab platform.

  • post transcriptional regulation of programmed cell death 4 PDCD4 mrna by the rna binding proteins human antigen r hur and t cell intracellular antigen 1 tia1
    Journal of Biological Chemistry, 2015
    Co-Authors: Callie P. Wigington, Jeenah Jung, Emily Rye, Sara L. Belauret, Akahne M. Philpot, Yue Feng, Philip J. Santangelo, Anita H. Corbett
    Abstract:

    Abstract Post-transcriptional processing of mRNA transcripts plays a critical role in establishing the gene expression profile of a cell. Such processing events are mediated by a host of factors, including RNA-binding proteins and microRNAs. A number of critical cellular pathways are subject to regulation at multiple levels that allow fine-tuning of key biological responses. Programmed cell death 4 (PDCD4) is a tumor suppressor and an important modulator of mRNA translation that is regulated by a number of mechanisms, most notably as a target of the oncomiR, miR-21. Here, we provide evidence for post-transcriptional regulation of PDCD4 by the RNA-binding proteins, HuR and TIA1. Complementary approaches reveal binding of both HuR and TIA1 to the PDCD4 transcript. Consistent with a model where RNA-binding proteins modulate the PDCD4 transcript, knockdown of HuR and/or TIA1 results in a significant decrease in steady-state PDCD4 mRNA and protein levels. However, fractionation experiments suggest that the mode of regulation of the PDCD4 transcript likely differs in the cytoplasm and the nucleus as the pool of PDCD4 mRNA present in the cytoplasm is more stable than the nuclear pool of PDCD4 transcript. We observe a competitive mode of binding between HuR and TIA1 on the PDCD4 transcript in the cytoplasm, suggesting that these two factors dynamically interact with one another as well as the PDCD4 transcript to maintain tight control of PDCD4 levels. Overall, this study reveals an additional set of regulatory interactions that modulate the expression of PDCD4, a key pro-apoptotic factor, and also reveals new insights into how HuR and TIA1 functions are integrated to achieve such regulation.

  • Post-transcriptional Regulation of Programmed Cell Death 4 (PDCD4) mRNA by the RNA-binding Proteins Human Antigen R (HuR) and T-cell Intracellular Antigen 1 (TIA1)
    The Journal of biological chemistry, 2014
    Co-Authors: Callie P. Wigington, Jeenah Jung, Emily Rye, Sara L. Belauret, Akahne M. Philpot, Yue Feng, Philip J. Santangelo, Anita H. Corbett
    Abstract:

    Post-transcriptional processing of mRNA transcripts plays a critical role in establishing the gene expression profile of a cell. Such processing events are mediated by a host of factors, including RNA-binding proteins and microRNAs. A number of critical cellular pathways are subject to regulation at multiple levels that allow fine-tuning of key biological responses. Programmed cell death 4 (PDCD4) is a tumor suppressor and an important modulator of mRNA translation that is regulated by a number of mechanisms, most notably as a target of the oncomiR, miR-21. Here, we provide evidence for post-transcriptional regulation of PDCD4 by the RNA-binding proteins, HuR and TIA1. Complementary approaches reveal binding of both HuR and TIA1 to the PDCD4 transcript. Consistent with a model where RNA-binding proteins modulate the PDCD4 transcript, knockdown of HuR and/or TIA1 results in a significant decrease in steady-state PDCD4 mRNA and protein levels. However, fractionation experiments suggest that the mode of regulation of the PDCD4 transcript likely differs in the cytoplasm and the nucleus as the pool of PDCD4 mRNA present in the cytoplasm is more stable than the nuclear pool of PDCD4 transcript. We observe a competitive mode of binding between HuR and TIA1 on the PDCD4 transcript in the cytoplasm, suggesting that these two factors dynamically interact with one another as well as the PDCD4 transcript to maintain tight control of PDCD4 levels. Overall, this study reveals an additional set of regulatory interactions that modulate the expression of PDCD4, a key pro-apoptotic factor, and also reveals new insights into how HuR and TIA1 functions are integrated to achieve such regulation. Background: PDCD4 is regulated by multiple mechanisms and is involved in tumor promotion. Results: PDCD4 mRNA is bound by the RNA-binding proteins HuR and TIA1, resulting in modulation of PDCD4 mRNA and protein levels. Conclusion: This study describes a dynamic regulation of PDCD4 mRNA via the 3′UTR. Significance: This work reveals an additional regulatory mechanism that modulates levels of the tumor suppressor PDCD4.