Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-kB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorageindependent cell growth in an NF-kB-dependent manner. We identified DNA copy-number gain and constitutive ubiquitination by a TNFa autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-kB-dependent activation mechanism as a novel approach to treat this disease.

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Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates

Double shell FeOOH/PPy on a diatomite ternary complex was assembled via two-step hydrothermal and in situ polymerization routes.

(2015) RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy, Autophagy, 11:7, 975-994, DOI: 10.1080/15548627.2015 Keywords: autophagy, cell death, endoplasmic reticulum stress, melanoma, RIPK1Abbreviations: 3-MA, 3-methyladenine; AMPK, AMP-activated protein kinase; ATF6, activating transcription factor 6; Baf A1, bafilomycin A 1 ; CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2: b; EIF2AK3/PERK, eukaryotic translation initiation factor 2-a kinase 3; ER, endoplasmic reticulum; ERN1/IRE1, endoplasmic reticulum to nucleus signaling 1; HSF1, heat shock transcription factor 1; HSPA5, heat shock 70kDa protein 5 (glucose-regulated protein: 78kDa); MAP2K1/MEK1, mitogenactivated protein kinase kinase 1; MAPK, mitogen-activated protein kinase; MAPK1/ERK2, mitogen-activated protein kinase 1; MAPK3/ERK1, mitogen-activated protein kinase 3; MAPK8/JNK1, mitogen-activated protein kinase 8; MAPK9/JNK2, mitogenactivated protein kinase 9; MAPK11/p38b, mitogen-activated protein kinase 11; MAPK12/p38g, mitogen-activated protein kinase 12; MAPK13/p38d, mitogen-activated protein kinase 13; MAPK14/p38a, mitogen-activated protein kinase 14; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; PRKAA1, protein kinase AMP-activated: a 1 catalytic subunit; RIPK1, receptor (TNFRSF)-interacting protein kinase 1; SQSTM1/p62, sequestosome 1; TG, thapsigargin; TM, tunicamycin; TNFRSF1A/ TNFR1, tumor necrosis factor receptor superfamily: member 1A; UPR, unfolded protein response; XBP1, x-box binding protein 1.Although RIPK1 (receptor [TNFRSF]-interacting protein kinase 1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in cell response to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIPK1 functions as an important prosurvival mechanism in melanoma cells undergoing pharmacological ER stress induced by tunicamycin (TM) or thapsigargin (TG) through activation of autophagy. While treatment with TM or TG upregulated RIPK1 and triggered autophagy in melanoma cells, knockdown of RIPK1 inhibited autophagy and rendered the cells sensitive to killing by TM or TG, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIPK1 enhanced induction of autophagy and conferred resistance of melanoma cells to TM-or TG-induced cell death. Activation of MAPK8/JNK1 or MAPK9/JNK2, which phosphorylated BCL2L11/BIM leading to its dissociation from BECN1/Beclin 1, was involved in TM-or TG-induced, RIPK1-mediated activation of autophagy; whereas, activation of the transcription factor HSF1 (heat shock factor protein 1) downstream of the ERN1/IRE1-XBP1 axis of the unfolded protein response was responsible for the increase in RIPK1 in melanoma cells undergoing pharmacological ER stress. Collectively, these results identify upregulation of RIPK1 as an important resistance mechanism of melanoma cells to TM-or TG-induced ...

The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.

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A facile and scalable method is developed to synthesize layered CuCo 2 O 4 nanosheets@MnO 2 nanoflakes core/shell arrays (CuCo 2 O 4 @MnO 2 NSCs) on Ni foam. Interestingly, the superstructures of core include well-arranged micrometer length rectangular two-dimensional (2D) nanosheets with high pore volume. Subsequently, MnO 2 nanoflakes are vertically grown on CuCo 2 O 4 nanosheets to form core/shell architecture. The electrochemical measurements demonstrate a high specific capacitance of 416 F g -1 at the current density of 1 A g -1 with excellent rate capability and remarkable cycling stability (92.1% retention after 4200 cycles). Impressively, the optimized CuCo 2 O 4 @MnO 2 //AG ACS cell can be cycled reversibly in a wide voltage region as high as 2.0 V and exhibits a specific capacitance of 78 F g -1 at a current density of 1 A g -1 with a maximum energy density of 43.3 Wh kg -1 . These encouraging results suggest that such unique CuCo 2 O 4 @MnO 2 NSCs architecture could be considered as one of the most promising candidates for energy storage devices with higher energy density delivery.