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Shengkan Jin

Publications and source records attributed to Shengkan Jin.

13 recordsLinked to original sources
PubMed2007

Autophagy regulates ageing in C. elegans.

The role of autophagy in ageing regulation has been suggested based on studies in C. elegans, in which knockdown of the expression of bec-1 (ortholog of the yeast and mammalian autophagy genes ATG6/VPS30 and beclin 1, respectively) shortens lifespan of the daf-2(e1370) mutant C. elegans. However, Beclin1/ATG6 is also known to be involved in other cellular functions in addition to autophagy. In the current study, we knocked down two other autophagy genes, atg-7 and atg-12, in C. elegans using RNAi. We showed that RNAi shortened the lifespan of both wild type and daf-2 mutant C. elegans, providing strong support for a role of autophagy in ageing regulation.

Aging↗
PubMed2007

Role of autophagy in cancer: management of metabolic stress.

Human breast, ovarian, and prostate tumors display allelic loss of the essential autophagy gene beclin1 with high frequency, and an increase in the incidence of tumor formation is observed in beclin1(+/-) mutant mice. These findings suggest a role for beclin1 and autophagy in tumor suppression; however, the mechanism by which this occurs has been unclear. Autophagy is a bulk degradation process whereby organelles and cytoplasm are engulfed and targeted to lysosomes for proteolysis,(1,2) There is evidence that autophagy sustains cell survival during nutrient deprivation through catabolism, but also that autophagy is a means of achieving cell death when executed to completion. If or how either of these diametrically opposing functions proposed for autophagy may be related to tumor suppression is unknown. We found that metabolic stress is a potent trigger of apoptotic cell death, defects in which enable long-term survival that is dependent on autophagy both in vitro and in tumors in vivo.(3) These findings raise the conundrum whereby inactivation of a survival pathway (autophagy) promotes tumorigenesis. Interestingly, when cells with defects in apoptosis are denied autophagy, this creates the inability to tolerate metabolic stress, reduces cellular fitness, and activates a necrotic pathway to cell death. This necrosis in tumors is associated with inflammation and enhancement of tumor growth, due to the survival of a small population of surviving, but injured, cells in a microenvironment that favors oncogenesis. Thus, by sustaining metabolism through autophagy during periods of metabolic stress, cells can limit energy depletion, cellular damage, and cell death by necrosis, which may explain how autophagy can prevent cancer, and how loss of a survival function can be tumorigenic.

Animals↗
PubMed2006

Autophagy is induced in CD4+ T cells and important for the growth factor-withdrawal cell death.

Autophagy is a tightly regulated catabolic mechanism that degrades proteins and organelles. Autophagy mediates programmed cell death under certain conditions. To determine the role of autophagy in T cells, we examined, in mouse CD4+ T cells, conditions under which autophagy is induced and alterations of the cell fate when autophagy is blocked. We have found that resting naive CD4+ T cells do not contain detectable autophagosomes. Autophagy can be observed in activated CD4+ T cells upon TCR stimulation, cytokine culturing, and prolonged serum starvation. Induction of autophagy in T cells requires JNK and the class III PI3K. Autophagy is inhibited by caspases and mammalian target of rapamycin in T cells. Interestingly, more Th2 cells than Th1 cells undergo autophagy. Th2 cells become more resistant to growth factor-withdrawal cell death when autophagy is blocked using either chemical inhibitors 3-methyladenine, or by RNA interference knockdown of beclin 1 and Atg7. Therefore, autophagy is an important mechanism that controls homeostasis of CD4+ T cells.

Animals↗
PubMed2006

Autophagy, mitochondrial quality control, and oncogenesis.

Cancer is a disease associated with aging. More than 80% of human cancers are diagnosed in people aged 55 years or older. Autophagy has recently been demonstrated to be a novel mechanism of tumor suppression. Interestingly, autophagy also plays an important role in the control of aging. Here we summarize the genetic studies of autophagy in tumorigenesis and aging, and propose that autophagy may suppress tumor development and prevent aging through a common mechanism involving mitochondrial surveillance.

Animals↗
PubMed2006

Cellular autophagy machinery is not required for vaccinia virus replication and maturation.

The origin of the primary membrane of the vaccinia virus, a double-membrane structure that surrounds the immature virions (IV), is not fully understood. Here we investigated whether the primary membrane originates from the autophagic membrane. Morphologic studies by electron microscopy (EM) showed no apparent difference in viral maturation in the autophagy-deficient cell lines, the atg5(-/-) mouse embryonic fibroblasts (MEFs) and the beclin1(-/-) embryonic stem (ES) cells, compared to their isogenic wild-type counterparts. Moreover, viral growth curves demonstrated that vaccinia viruses replicate and mature in the autophagy-deficient cell lines as efficiently as they do in their isogenic wild type counterpart cells. This study indicates that the cellular autophagy machinery is not required for the life-cycle of vaccinia virus, suggesting that the primary vaccinia viral membrane does not originate from the autophagic membrane.

Animals↗
PubMed2006

Elongation factor-2 kinase regulates autophagy in human glioblastoma cells.

Elongation factor-2 kinase (eEF-2 kinase), also known as Ca(2+)/calmodulin-dependent kinase III, regulates protein synthesis by controlling the rate of peptide chain elongation. The activity of eEF-2 kinase is increased in glioblastoma and other malignancies, yet its role in neoplasia is uncertain. Recent evidence suggests that autophagy plays an important role in oncogenesis and that this can be regulated by mammalian target of rapamycin (mTOR). Because eEF-2 kinase lies downstream of mTOR, we studied the role of eEF-2 kinase in autophagy using human glioblastoma cell lines. Knockdown of eEF-2 kinase by RNA interference inhibited autophagy in glioblastoma cell lines, as measured by light chain 3 (LC3)-II formation, acidic vesicular organelle staining, and electron microscopy. In contrast, overexpression of eEF-2 kinase increased autophagy. Furthermore, inhibition of autophagy markedly decreased the viability of glioblastoma cells grown under conditions of nutrient depletion. Nutrient deprivation increased eEF-2 kinase activity and decreased the activity of S6 kinase, suggesting an involvement of mTOR pathway in the eEF-2 kinase regulation of autophagy. These results suggest that eEF-2 kinase plays a regulatory role in the autophagic process in tumor cells; and eEF-2 kinase is a downstream member of the mTOR signaling; eEF-2 kinase may promote cancer cell survival under conditions of nutrient deprivation through regulating autophagy. Therefore, eEF-2 kinase may be a part of a survival mechanism in glioblastoma and targeting this kinase may represent a novel approach to cancer treatment.

Autophagy↗
PubMed2006

Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways.

Over the past 10 years the signal transduction networks for p53, IGF-1-AKT, and TOR pathways have been assembled in worms, flies, and mammals, and their functions elucidated. In the past 1-2 years a number of genes and their proteins have been identified that permit extensive communication and coordination between these pathways. These three pathways are involved in sensing and integrating signals arising from nutrient and growth factor availability, signals from sensory and sexual organs, and intrinsic and extrinsic stress signals. In turn these pathways regulate cell growth, proliferation, and death. These networks are central to our understanding of a variety of physiological and pathological conditions, including cancer, diabetes, and longevity.

Animals↗
PubMed2006

Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis.

Defective apoptosis renders immortalized epithelial cells highly tumorigenic, but how this is impacted by other common tumor mutations is not known. In apoptosis-defective cells, inhibition of autophagy by AKT activation or by allelic disruption of beclin1 confers sensitivity to metabolic stress by inhibiting an autophagy-dependent survival pathway. While autophagy acts to buffer metabolic stress, the combined impairment of apoptosis and autophagy promotes necrotic cell death in vitro and in vivo. Thus, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors, but this necrosis is associated with inflammation and accelerated tumor growth. Thus, autophagy may function in tumor suppression by mitigating metabolic stress and, in concert with apoptosis, by preventing death by necrosis.

Animals↗
PubMed2005

p53, Autophagy and tumor suppression.

Autophagy was recently established as a novel tumor suppression mechanism, which stimulated a wave of investigations that were aimed at understanding exactly how autophagy prevents tumorigenesis, as well as to determine to what extent autophagy is implicated in human cancers. Autophagy might exert its tumor suppression function at the subcellular level by removing defective cytoplasmic components, such as damaged mitochondria. In addition, it might function at the cellular level by helping in the orderly removal of damaged cells. Previous studies indicated that autophagy is compromised in human breast, ovarian and prostate cancers. Recent research revealed that autophagy is activated by p53, a critical tumor suppressor that is involved in most, if not all, tumorigenesis. This study places autophagy in a broader context of human cancers. Future work elucidating the role of autophagy in the p53 circuit and p53 function might provide more insight into tumorigenesis and targeted cancer chemotherapy.

Autophagy↗
PubMed2005

The coordinate regulation of the p53 and mTOR pathways in cells.

Cell growth and proliferation requires an intricate coordination between the stimulatory signals arising from nutrients and growth factors and the inhibitory signals arising from intracellular and extracellular stresses. Alteration of the coordination often causes cancer. In mammals, the mTOR (mammalian target of rapamycin) protein kinase is the central node in nutrient and growth factor signaling, and p53 plays a critical role in sensing genotoxic and other stresses. The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process. Moreover, the mechanisms by which p53 regulates mTOR involves AMP kinase activation and requires the tuberous sclerosis (TSC) 1/TSC2 complex, both of which respond to energy deprivation in cells. In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein. Thus, p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation, and death.

AMP-Activated Protein Kinases↗
PubMed2003

Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.

Animals↗
PubMed2003

CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals.

Recently a Drosophila p53 protein has been identified that mediates apoptosis via a novel pathway involving the activation of the Reaper gene and subsequent inhibition of the inhibitors of apoptosis (IAPs). The present study found that CIAP1, a major mammalian homolog of Drosophila IAPs, is irreversibly inhibited (cleaved) during p53-dependent apoptosis and this cleavage is mediated by a serine protease. Serine protease inhibitors that block CIAP1 cleavage inhibit p53-dependent apoptosis. Furthermore, activation of the p53 protein increases the transcription of the HTRA2 gene, which encodes a serine protease that interacts with CIAP1 and potentiates apoptosis. These results demonstrate that the mammalian p53 protein may activate apoptosis through a novel pathway functionally similar to that in Drosophila, which involves HTRA2 and subsequent inhibition of CIAP1 by cleavage.

Animals↗