The Shc protein RAI promotes an adaptive cell survival program in hypoxic neuroblastoma cells

Criscuoli, Mattia; Filippi, Irene; Osti, Daniela; Aldinucci, Carlo; Guerrini, Giuditta; Pelicci, Giuliana; Carraro, Fabio; Naldini, Antonella

doi:10.1002/jcp.26247

Cited by 6 publications

(12 citation statements)

References 55 publications

(86 reference statements)

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“…Previous reports indicate that the adapter protein Rai positively controls the survival of neuroblastoma cells (Miyake et al, 2002; Miyake et al, 2005; Miyake, Ohira, Nakagawara, & Sakai, 2009) and that Rai plays a protective role against cerebral ischemia (Troglio et al, 2004). More interestingly, we have recently shown that Rai is relevant in protecting neuroblastoma cells against cell death induced by hypoxia by promoting HIF‐1α accumulation and HIF‐1α‐related signaling (Criscuoli et al, 2018). We report here that Rai promotes HIF‐1 accumulation also in hypoxic T cells, suggesting that Rai may be involved in the modulation of HIF‐1α expression.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that hypoxia induces T cell death through the activation of a proapoptotic program and the involvement of the p66Shc protein (Carraro et al, 2007;Naldini et al, 2010). More recently, we have reported that the expression of the Shc protein Rai protects neuroblastoma cells against cell death induced by hypoxia (Criscuoli et al, 2018). (Raman, Chen, & Cobb, 2007).…”

Section: Rai Protects T Cells Under Hypoxia By Activating Pro-survimentioning

confidence: 96%

“…2.6 | Glucose and lactate determination Glucose uptake and lactate production were analyzed by RAPIDPoint 500 Siemens and calculated as previously reported (Criscuoli et al, 2018).…”

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confidence: 99%

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The Shc protein Rai enhances T‐cell survival under hypoxia

Criscuoli

Ulivieri

Filippi

et al. 2020

Journal Cellular Physiology

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Hypoxia occurs in physiological and pathological conditions. T cells experience hypoxia in pathological and physiological conditions as well as in lymphoid organs. Indeed, hypoxia‐inducible factor 1α (HIF‐1α) affects T cell survival and functions. Rai, an Shc family protein member, exerts pro‐survival effects in hypoxic neuroblastoma cells. Since Rai is also expressed in T cells, we here investigated its role in hypoxic T cells. In this work, hypoxia differently affected cell survival, proapoptotic, and metabolic programs in T cells, depending upon Rai expression. By using Jurkat cells stably expressing Rai and splenocytes from Rai−/−mice, we demonstrated that Rai promotes T cell survival and affects cell metabolism under hypoxia. Upon exposure to hypoxia, Jurkat T cells expressing Rai show (a) higher HIF‐1α protein levels; (b) a decreased cell death and increased Akt/extracellular‐signal‐regulated kinase phosphorylation; (c) a decreased expression of proapoptotic markers, including caspase activities and poly(ADP‐ribose) polymerase cleavage; (d) an increased glucose and lactate metabolism; (e) an increased activation of nuclear factor‐kB pathway. The opposite effects were observed in hypoxic splenocytes from Rai−/−mice. Thus, Rai plays an important role in hypoxic signaling and may be relevant in the protection of T cells against hypoxia.

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Section: Discussionmentioning

confidence: 99%

Section: Rai Protects T Cells Under Hypoxia By Activating Pro-survimentioning

confidence: 96%

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The Shc protein Rai enhances T‐cell survival under hypoxia

Criscuoli

Ulivieri

Filippi

et al. 2020

Journal Cellular Physiology

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“…Total RNA was extracted following manufacturer's instructions. Complementary DNA was synthesized using iScript™cDNA Synthesis Kit (Bio-Rad Laboratories) and reverse transcription quantitative polymerase chain reaction was performed using SsoAdvanced™ Universal SYBR ® Green Supermix (Bio-Rad Laboratories), using an iQ™ 5 Muticolor Real-Time PCR Detection System (Bio-Rad Laboratories) as previously described (Criscuoli et al, 2017). Primers for SMO, CAXII, and β-actin were designed with Primer BLAST program (NCBI, 2016).…”

Section: Reverse Transcription Quantitative Polymerase Chain Reactionmentioning

confidence: 99%

Inhibition of smoothened in breast cancer cells reduces CAXII expression and cell migration

Guerrini

Criscuoli

Filippi

et al. 2018

Journal Cellular Physiology

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Breast cancer (BC) relapse and metastasis are the leading cause of death and, together with drug resistance, keep mortality still high. The Hedgehog (Hh) pathway is expressed during embryogenesis, organogenesis and in adult tissue homeostasis and its aberrant activation is often associated with cancer. Carbonic anhydrase (CA) enzymes are important during development; they play a key role in controlling several cellular mechanisms, such as pH regulation, survival, and migration, and they are aberrantly expressed in cancer. The goal of this study was to investigate the interplay between the Hh pathway and CAXII in terms of BC cell migration. We here demonstrated that smoothened (SMO) silencing resulted in a reduction of CAXII expression at mRNA and protein level. This led to a decrease in cell migration, which was restored when cells were treated with an SMO agonist, Sag dihydrochloride (SAG), but not when cells were cotreated with SAG and the CAs inhibitor Acetazolamide. This suggested that the ability of SAG to promote cell migration was impaired when CAXII was inhibited. The reduction was also confirmed within hypoxic and inflammatory microenvironment, typical of BC, indicating a key role of the Hh pathway in controlling CAXII expression. Our results may contribute to further understand the physiology of BC cells and indicate that the Hh pathway controls BC cell migration and cell invasion also through CAXII, with important implications in identifying novel therapeutic targets.

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“…7 ShcA plays a role in insulin signaling, stress resistance and energy metabolism. 8 ShcA exists in three splicing isoforms: p46shc, p52shc, and p66shc 9 . The p52 and p46 forms of ShcA are able to activate the Ras and MAP kinase pathway.…”

Section: Introductionmentioning

confidence: 99%

The Src homology and collagen A (ShcA) adaptor protein may participate in the pathogenesis of membranous lupus nephritis

Cao

Liu

et al. 2018

Lupus

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The Src homology and collagen A (ShcA) adaptor protein that binds to tyrosine kinase receptors. ShcA plays a role in insulin signaling, stress resistance and energy metabolism. The 66-kDa Src homology 2 domain-containing protein (p66shc) belongs to the ShcA family and has been associated with reactive oxygen species (ROS); increased ROS is involved in the pathology of lupus nephritis (LN). However, whether ShcA can act as a biomarker for oxidative injury in LN is unknown. This study is aimed to investigate the ShcA expression in kidney tissues from patients presenting with LN and the association between ShcA expression and clinical parameters. Renal biopsy tissues were obtained from 62 LN, 20 primary membranous nephropathy (MN) and 10 other secondary MN patients. ShcA was measured by immunofluorescence. The expression of ShcA in the membranous lupus nephritis (class V) group showed a higher trend but there were no significant differences compared with pure mesangial disease (class II) and proliferative (Class III/IV) lupus nephritis. ShcA deposits were negative in primary and other secondary MN. ShcA might act as a new biomarker and a diagnostic tool to identify membranous lupus nephritis with other MN.

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The Shc protein RAI promotes an adaptive cell survival program in hypoxic neuroblastoma cells

Cited by 6 publications

References 55 publications

The Shc protein Rai enhances T‐cell survival under hypoxia

The Shc protein Rai enhances T‐cell survival under hypoxia

Inhibition of smoothened in breast cancer cells reduces CAXII expression and cell migration

The Src homology and collagen A (ShcA) adaptor protein may participate in the pathogenesis of membranous lupus nephritis

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