The Receptor Interacting Protein 1 Inhibits p53 Induction through NF-κB Activation and Confers a Worse Prognosis in Glioblastoma

Park, Seong‐Mi; Hatanpaa, Kimmo J.; Xie, Yang; Mickey, Bruce; Madden, Christopher J.; Raisanen, Jack M.; Ramnarain, Deepti B.; Xiao, Guanghua; Saha, Debabrata; Boothman, David A.; Zhao, Dawen; Bachoo, Robert; Pieper, Russell O.; Habib, Amyn A.

doi:10.1158/0008-5472.can-08-4079

Cited by 149 publications

(134 citation statements)

References 51 publications

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“…However, in contrast with previous reports in other types of cells (35,37), inhibition of p53 does not appear to play a major role in RIP1-mediated proliferation of melanoma cells, as knockdown of RIP1 similarly inhibited cell proliferation in p53-null melanoma cells (ME4405 cells; ref. 38).…”

Section: Discussioncontrasting

confidence: 91%

RIP1 Kinase Is an Oncogenic Driver in Melanoma

et al. 2015

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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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Section: Discussioncontrasting

confidence: 91%

RIP1 Kinase Is an Oncogenic Driver in Melanoma

et al. 2015

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“…2,4,59 In particular, the role of RIPK1 in apoptosis and necrosis of cancer cells in response to therapeutic agents is being increasingly reported. 2,4 Indeed, overexpression of RIPK1 causes apoptosis in many types of cells, 51,60 suggesting that RIPK1 may function primarily as an antisurvival protein in cells. Nevertheless, ripk1 ¡/¡ mice display extensive apoptosis in selected tissues and die at age 1 to 3 d, suggesting that RIPK1 plays a crucial role in cell survival in a context-and cell typedependent fashion.…”

Section: Discussionmentioning

confidence: 99%

RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

et al. 2015

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(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 ...

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“…17 Indeed, in A549 and H460 cells that have wild-type p53, RIP1 knockdown elevated the protein expression of p53 together with its targets p21 and MDM2 (Figure 1d and Supplementary Figure 1c). With RIP1 stable knockdown, p21 induction was also seen in H23 cells with a p53 mutation (M246I) capable of activating p21 expression, 18 but p21 induction was not observed in p53 inactive mutant (R273L) H2009 and p53 null H1299 cells (Supplementary Figure 1c).…”

Section: Resultsmentioning

confidence: 90%

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

Chen

Wang²,

Bai

et al. 2014

Cell Death Differ

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Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor c coactivator-1a (PGC-1a) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy. A cell's metabolism is optimized for its function and adapts to environmental changes; therefore, it is pivotal to differentiation, proliferation, survival and death. In the presence of ample oxygen, cancer cells prefer glycolysis over mitochondrial respiration for energy supply, which is known as the Warburg effect or aerobic glycolysis.1,2 Although aerobic glycolysis was originally thought to complement impaired mitochondrial respiration, recent investigations suggest that it is a driving force in cancer cell transformation and proliferation. 3,4 In coordination with the tricarboxylic acid cycle and mitochondrial respiration, cancer cells increase glycolysis to support their rapid proliferation. This 'metabolic transformation' in cancer cells not only meets their energy requirements but also provides the building blocks for synthesis of biomass and for maintenance of redox homeostasis. 5,6 Thus, the metabolic transformation is believed to offer cancer cells a selective growth advantage compared with their normal counterparts and to contribute to drug resistance. Many oncogenes such as c-Myc and Akt, and tumor suppressors such as p53 are involved in the regulation of glycolysis and mitochondrial metabolism, serving as evidence of the necessity for metabolic adaptation in cancer cells. 7,8 However, how metabolic transformation is precisely regulated needs further elucidation.Receptor-interacting protein 1 (RIP1) is a serine/threonine kinase with functions in cell proliferation, survival and death.9-11 The role of RIP1 in cell survival is achieved mainly through its function as an adaptor in signal pathways, such as NF-kB and PI3K/Akt, that suppress apoptosis. The kinase activity of RIP1 is involved in programmed necrosis or necroptosis.12 Although RIP1 can translocate to the mitochondria in certain circumstances and can modulate ADP/ ATP exchange and the production of mitochondrial reactive oxygen species (ROS), [13][14][15][16] whether RIP1 regulates cell energy homeostasis is unknown.In an attempt to investigate the role of RIP1 in cell proliferation, we uncovered a function for this protein in...

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The Receptor Interacting Protein 1 Inhibits p53 Induction through NF-κB Activation and Confers a Worse Prognosis in Glioblastoma

Cited by 149 publications

References 51 publications

RIP1 Kinase Is an Oncogenic Driver in Melanoma

RIP1 Kinase Is an Oncogenic Driver in Melanoma

RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

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