Upregulation of RNase E activity by mutation of a site that uncompetitively interferes with RNA binding

Go, Hayoung,Moore, Christopher J.,Lee, Minho,Shin, Eunkyoung,Jeon, Che Ok,Cha, Chang-Jun,Han, Seung Hyun,Kim, Su-Jin,Lee, Sang-Won,Lee, Younghoon,Ha, Nam-Chul,Kim, Yong-Hak,Cohen, Stanley N.,Lee, Kang LANDES BIOSCIENCE 2011 RNA biology Vol.8 No.6

A theoretical model for p53 dynamics: identifying optimal therapeutic strategy for its activation and stabilization.

Kim, Do-Hyun,Rho, Kyoohyoung,Kim, Sunghoon Landes Bioscience 2009 Cell Cycle Vol.8 No.22

<P>The activation and stabilization of tumor suppressor p53 are very important in preventing cells from becoming cancerous. Hence, many experimental works have been carried out to investigate p53's dynamics through its interactions with other proteins and its therapeutic applications for the treatment of cancers. In this work, by analyzing a theoretical model, we attempt to search for an optimal therapeutic strategy that guarantees the activation and stabilization of p53. For this purpose, we introduce a new mathematical model including oncogene activation and ARF, which are recognized as crucial for tumor suppression but have not yet been considered in most theoretical works. Through mathematical modeling and numerical simulations, we confirm several important properties of p53 dynamics: the role of the oncogene-mediated activation of ARF as an important factor for the activation and stabilization of p53, the necessity of time delays in negative feedback loops to guarantee sustained p53 oscillations, and the digital behavior of p53 pulses. Furthermore, we propose that the binding of ARF to Mdm2 and enhancing the degradation of Mdm2 is an efficient strategy for therapeutic targeting, which may assure the activation and stabilization of p53.</P>

Photodynamic therapy with 9-hydroxypheophorbide alpha on AMC-HN-3 human head and neck cancer cells: induction of apoptosis via photoactivation of mitochondria and endoplasmic reticulum.

Chung, Phil-Sang,He, Peijie,Shin, Jang-In,Hwang, Hee-Jun,Lee, Sang Joon,Ahn, Jin-Chul Landes Bioscience 2009 Cancer Biology & Therapy Vol.8 No.14

<P>Skin phototoxicity is one of the main side effects of photodynamic therapy (PDT). To overcome this problem, some new photosensitizers have been developed with longer absorbance wavelengths and shorter half-life in the body. In this study, we investigated the mechanism of PDT mediated by a new chlorophyll derivative photosensitizer, 9-hydroxypheophorbide alpha (9-HPbD), on AMC-HN-3 cancer cells. Phototoxicity and apoptosis on AMC-HN-3 cells induced by 9-HPbD was exhibited in a time- and dose-dependent manner. Mitochondria and endoplasmic reticulum (ER) were observed as preferential sites of 9-HPbD accumulation. Photoactivation of 9-HPbD-loaded AMC-HN-3 cells led to a rapid generation of reactive oxygen species (ROS) at 30 min, followed by a loss of mitochondrial membrane potential (MMP) at 2 h, translocation of apoptosis-inducing factor (AIF) at 2 h, and the release of cytochrome c at 3 h following PDT. Caspase-12, an important caspase involved in ER-induced apoptosis, and C/EBP homologous protein (CHOP), an ER stress inducible transcription factor, were also upregulated after PDT (3-12 h and 6-12 h, respectively). Subsequently, activation of caspase-9 at 6 h, caspase-3 and PARP at 12 h also occurred in PDT-treated AMC-HN-3 cells. The above observations demonstrate that both mitochondria and ER serve not only as the sites of sensitizer binding, but also the subcellular targets of 9-HPbD-PDT, effective activation of which is responsible for 9-HPbD PDT-induced apoptosis in AMC-HN-3 cells.</P>

Macroautophagy in homeostasis of pancreatic beta-cell.

Jung, Hye Seung,Lee, Myung-Shik Landes Bioscience 2009 AUTOPHAGY Vol.5 No.2

<P>Diabetes mellitus is characterized by decreased insulin secretion and action. Decreased insulin secretion results from a reduction in pancreatic beta-cell mass and function. Apoptosis, oxidative stress, mitochondrial dysfunction, and ER stress responses including JNK activation have been suggested as mechanisms of the changes of pancreatic beta-cells in type 2 diabetes, however, the underlying causes were not clearly elucidated. Autophagy is an intracellular process that plays a crucial role in cellular homeostasis through degradation and recycling of organelles constitutively or in response to the environmental condition. We studied the role of autophagy in pancreatic beta-cells using mice with beta-cell-specific deletion of the Atg7 (autophagy-related 7) gene. Atg7-mutant mice showed increased apoptosis and decreased proliferation of beta-cells with resultant reduction in beta-cell mass. Pancreatic insulin content was decreased due to the decreased beta-cell mass and reduced number of insulin granules. Morphological analysis of beta-cells revealed accumulation of ubiquitinated proteins, swollen mitochondria, and distended ER. Insulin secretory function ex vivo was also impaired. As a result, autophagy-deficient mice showed hypoinsulinemia and hyperglycemia. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic beta-cells. Here we discuss the significance of autophagy in pancreatic beta-cells with its potential relevance to the development of diabetes.</P>

TRPC channels as STIM1-regulated SOCs.

Yuan, Joseph P,Kim, Min Seuk,Zeng, Weizhong,Shin, Dong Min,Huang, Guo,Worley, Paul F,Muallem, Shmuel Landes Bioscience 2009 Channels Vol.3 No.4

<P>Store-operated Ca(2+) channels (SOCs) are Ca(2+) influx channels at the plasma membrane whose opening is determined by the level of Ca(2+) stored in the endoplasmic reticulum lumen. SOCs are activated in response to receptor-mediated or passive depletion of ER Ca(2+) to regulate many Ca(2+)-dependent cellular functions. Early work implicated the TRPC channels as SOCs. More recently, it was found that the Orai channels mediate the CRAC current and that the Ca(2+) binding protein STIM1 functions as the ER Ca(2+) sensor that mediates activation of the SOCs in response to depletion of ER Ca(2+). Key questions are whether both TRPC and Orai channels are opened by STIM1 and the molecular mechanism by which STIM1 opens the SOCs. Ample biochemical and functional evidence indicate interaction of the TRPC channels with STIM1. Furthermore, it was found that STIM1 gates TRPC channels by electrostatic interaction of STIM1(K684,K685) in the polybasic domain of STIM1 with two negative charges (aspartates or glutamates) that are conserved in all TRPC channels. Charge mutants of STIM1(K684,K685) and TRPC1(D639,D640) and TRPC3(D697,D698) were used to develop further direct evidence for the function of TRPC channels as SOCs. The evidence in favor of TRPC channels as SOCs are discussed.</P>

p30 DBC is a potential regulator of tumorigenesis.

Kim, Ja-Eun,Chen, Junjie,Lou, Zhenkun Landes Bioscience 2009 Cell Cycle Vol.8 No.18

<P>Tumorigenesis is a multistep process controlled by a number of proteins involved in diverse pathways. Traditionally, proteins are either considered as oncogenes, which promote tumorigenesis or as tumor suppressors, which prevent tumorigenesis. However, recent studies revealed quite a few proteins that could function as oncogene as well as tumor suppressor. A new member of such proteins is p30 DBC (deleted in breast cancer 1, also called DBC1). p30 DBC is one of the proteins involved in tumorigenesis that does not clearly adhere to either descriptions. Several studies show that p30 DBC is involved in cell proliferation, apoptosis and histone modification, all processes important for regulating tumorigenesis. However, there are other conflicting results regarding how p30 DBC contributes to tumorigenesis. The most interesting aspect of this is that p30 DBC is a strong inhibitor of SIRT1 protein deacetylase, whose exact role in tumorigenesis is currently under debate. This review summarizes the current understandings on p30 DBC functions, with a focus on the proposed roles of p30 DBC in tumorigenesis.</P>

TMAP/CKAP2 is essential for proper chromosome segregation.

Hong, Kyung Uk,Kim, Eunhee,Bae, Chang-Dae,Park, Joobae Landes Bioscience 2009 Cell Cycle Vol.8 No.2

<P>Tumor-associated microtubule-associated protein (TMAP), also known as cytoskeleton associated protein 2 (CKAP2), is a novel mitotic spindle-associated protein which is frequently up-regulated in various malignances. However, its cellular functions remain unknown. Previous reports suggested that the cellular functions of TMAP/CKAP2 pertain to regulation of the dynamics and assembly of the mitotic spindle. To investigate its role in mitosis, we studied the effects of siRNA-mediated depletion of TMAP/CKAP2 in cultured mammalian cells. Unexpectedly, TMAP/CKAP2 knockdown did not result in significant alterations of the spindle apparatus. However, TMAP/CKAP2-depleted cells often exhibited abnormal nuclear morphologies, which were accompanied by abnormal organization of the nuclear lamina, and chromatin bridge formation between two daughter cell nuclei. Time lapse video microscopy revealed that the changes in nuclear morphology and chromatin bridge formations observed in TMAP/CKAP2-depleted cells are the result of defects in chromosome segregation. Consistent with this, the spindle checkpoint activity was significantly reduced in TMAP/CKAP2-depleted cells. Moreover, chromosome missegregation induced by depletion of TMAP/CKAP2 ultimately resulted in reduced cell viability and increased chromosomal instability. Our present findings demonstrate that TMAP/CKAP2 is essential for proper chromosome segregation and for maintaining genomic stability.</P>

Insulin receptor signaling for the proliferation of pancreatic 관-cells: Involvement of Ca (2+) second messengers, IP3, NAADP and cADPR.

Shawl, Asif Iqbal,Park, Kwang-Hyun,Kim, Uh-Hyun Landes Bioscience 2009 Islets Vol.1 No.3

<P>Insulin has an autocrine/paracrine role through insulin receptors in pancreatic 관-cells. Herein, we show the insulin receptor signaling pathway underlying CD38/ADPR-cyclase activation for NAADP/cADPR formation to induce Ca2+ rise, ultimately resulting in 관-cell proliferation. Binding of insulin on insulin receptors leads to the activation of IRS/Akt/PI3K/PLC. Activation of PLC generates IP3 and DAG; the former induces Ca (2+) release, resulting in activation of CD38/ADPR-cyclase for cADPR production via cGMP-dependent mechanism and the latter activates PKC, resulting in activation of ADPR-cyclase for NAADP synthesis. The NAADP-induced Ca (2+) signal is required for IP3-induced Ca (2+) release from the ER. CD38 plays an important role in insulin receptor signaling in 관-cells by reflecting a declined sustained Ca (2+) signal, cADPR levels, and 관-cell proliferation in response to insulin in CD38 (-/-) islets. However, evidence indicates that a hitherto-unidentified ADPR cyclase in addition to CD38 participates in insulin-induced signaling through cADPR and NAADP synthesis. In conclusion, insulin receptor signaling in 관-cells employs three Ca (2+) signaling messengers, IP3, NAADP, and cADPR through a complex but concerted action of signaling molecules for Ca2+ signaling, which is involved in the proliferation of the islets.</P>

p21Cip1 regulation by ERK2 A post-translational mechanism that relays a proliferation signal.

Hwang, Chae Young,Kwon, Ki-Sun Landes Bioscience 2009 Cell Cycle Vol.8 No.22

Interplay between autophagy and apoptosis in TrkA-induced cell death.

Dadakhujaev, Shorafidinkhuja,Jung, Eun Joo,Noh, Hae Sook,Hah, Young-Sool,Kim, Chang Jae,Kim, Deok Ryong Landes Bioscience 2009 AUTOPHAGY Vol.5 No.1

<P>Autophagy is a self-eating process to eradicate damaged proteins or organelles in cells. This process begins with formation of a double-membrane structure, called an autophagosome, which can sequester soluble proteins and organelles eventually degraded by lysosomal proteases after fusion with the lysosome. Autophagy was initially identified as a cell survival mechanism under stress conditions such as nutrient deprivation. More recently, it is also considered as type-II programmed cell death. In our recent report, we observed that overexpression of TrkA caused massive cell death via both apoptosis and autophagy. Overexpression of TrkA abated catalase activity and subsequently resulted in the production of a large amount of reactive oxygen species in cells. These consequences led to autophagic cell death. The autophagic cell death in TrkA-overexpressing cells was validated by GFP-LC3 dot formation, production of autophagosomes or acidic vacuoles, LC3 lipidation, and depletion of autopahgy-related genes. In addition, we also observed some evidence for apoptosis in TrkA-expressing cells. Many cells expressing TrkA exhibited annexin V-positive staining, activation of caspase-7 and BAX. Moreover, TrkA activated the JNK pathway, leading to phosphorylation of H2AX. In this report, we suggest that two cell death mechanisms occur simultaneously and interlink with each other. The JNK-calpain pathway might be a central process to mediate the two processes in TrkA-overexpressing cells, although further study still remains to prove the interplay between autophagy and apoptosis.</P>