The cleavage of HuR interferes with its transportin-2-mediated nuclear import and promotes muscle fiber formation

Beauchamp, Pascal; Nassif, Christina; Hillock, S.; Giessen, Kate van der; Roretz, Christopher von; Jasmin, Bernard J.; Gallouzi, Imed Eddine

doi:10.1038/cdd.2010.34

Cited by 50 publications

(88 citation statements)

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“…HuR shuttles between the nucleus and the cytoplasm, and while only a fraction of it (B10-20%) localizes to the cytoplasm, 36,37 it is in this compartment where HuR exercises its main biological effects. [15][16][17]30,[38][39][40] Our recent papers 18,24,25,41 strengthen this idea and show that the HuR-CPs, generated from B50% of cytoplasmic HuR, are both sufficient and necessary for HuR-mediated effects. 18 However, as not all cytoplasmic HuR is cleaved, wt HuR and both of its CPs are all present simultaneously, and thus may be affected by one another when exercising their effects.…”

Section: Discussionmentioning

confidence: 80%

“…18,24,25 This raised the question of how cleaving only a portion of this highly expressed protein could have such a dramatic impact on cell fate. HuR shuttles between the nucleus and the cytoplasm, and while only a fraction of it (B10-20%) localizes to the cytoplasm, 36,37 it is in this compartment where HuR exercises its main biological effects.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, HuR-CP1 promotes muscle development in murine myoblasts by enabling the cytoplasmic accumulation of wt HuR. 25 HuR-CP1 causes a similar effect in response to lethal stress, by binding to the import factor transportin-2 and augmenting cytoplasmic localization of HuR. 41 Here we show that together the two CPs are capable of stabilizing caspase-9 mRNA, even to a greater extent than wtHuR, and our previous data also indicate that the two CPs of HuR are most potent for inducing apoptosis when present simultaneously.…”

Section: Discussionmentioning

confidence: 99%

“…This is comparable to observations made by Talwar et al 35 that HuR-CP1, and not wtHuR, inhibits the translation of c-myc mRNA. As previous observations indicated that HuR-CPs exercise their function by associating with various protein partners, 18,25 it would be interesting to determine if their capacity to post-transcriptionally regulate gene expression also depends on other ligands. HuRmediated effects can involve microRNAs, 42,43 which are established inhibitors of gene expression involved in a variety of processes including apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…18,24 Physiological significance of this cleavage, which occurs for approximately 50% of cytoplasmic HuR, was shown in the process of muscle development. 25 The significance of HuR cleavage in apoptosis was demonstrated by the fact that a non-cleavable mutant (HuR D226A ) of HuR failed to rescue apoptosis in cells depleted of endogenous HuR. 18 In addition, the expression of these HuR-CPs can stimulate apoptosis in the presence of a non-lethal stress (conditions under which apoptosis is not engaged and HuR cleavage does not occur).…”

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Apoptotic-induced cleavage shifts HuR from being a promoter of survival to an activator of caspase-mediated apoptosis

et al. 2012

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Little is known about the cellular mechanisms modulating the shift in balance from a state of survival to cell death by caspasemediated apoptosis in response to a lethal stress. Here we show that the RNA-binding protein HuR has an important function in mediating this switch. During caspase-mediated apoptosis, HuR is cleaved to generate two cleavage products (CPs). Our data demonstrate that the cleavage of HuR switches its function from being a prosurvival factor under normal conditions to becoming a promoter of apoptosis in response to a lethal stress. In the absence of an apoptotic stimuli, HuR associates with and promotes the expression of caspase-9 and prothymosin a (ProT) mRNAs, and pro-and antiapoptotic factors, respectively, both of which have been characterized as important players in determining cell fate. During the early steps of caspase-mediated apoptosis, however, the level of caspase-9 protein increases, while ProT remains unchanged. Under these conditions, the two HuR-CPs selectively bind to and stabilize caspase-9 mRNA, but do not bind to ProT. Hence, taken together, our data show that by maintaining a threshold of expression of proapoptotic factors such as caspase-9 in response to a lethal stress, the HuR-CPs help a cell to switch from resisting death to undergoing apoptosis.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Apoptotic-induced cleavage shifts HuR from being a promoter of survival to an activator of caspase-mediated apoptosis

et al. 2012

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Identification of Distinct Genetic Profiles of Palindromic Rheumatism Using Whole‐Exome Sequencing

Zheng

Wang

Sun

et al. 2023

Arthritis & Rheumatology

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ObjectivePrevious studies underline the genetic susceptibility in the pathogenesis of Palindromic Rheumatism (PR), but the known PR loci only explain partially the disease's genetic background. We aim to genetically identify PR by whole exome sequencing (WES).MethodsThis multi‐center prospective study was conducted in ten Chinese specialized rheumatology centers between September 2015 and January 2020. WES was performed in a PR cohort (185 PR cases and 272 healthy controls). PR patients were divided in to ACPA‐ PR and ACPA+ PR subgroups according to ACPA titer (cut‐off value: 20UI/I). Whole‐exome association analysis was conducted for the WES data. HLA imputation was used to type HLA genes. The polygenic risk score (PRS) was further used to measure the genetic correlations between PR and Rheumatoid Arthritis (RA) , and the genetic correlations between ACPA‐ PR and ACPA+ PR.ResultsA total of 185 patients with PR were enrolled. ACPA was found positive in 50 out of 185 PR patients (27.02%), and 135 PR patients were ACPA negative (72.98%). 8 novel loci (ACPA‐ PR: ZNF503, RPS6KL1, HOMER3, HLA‐DRA; ACPA+ PR: RPS6KL1, TNPO2, WASH2P, FANK1) and three HLA alleles (ACPA‐ PR:HLA‐DRB1*0803, HLA‐DQB1; ACPA+ PR: HLA‐DPA1*0401) were found to be associated with PR surpassing genome‐wide significance (p<5x10‐8). Furthermore, PRS analysis showed PR and RA were not similar (R2<0.025), while ACPA+ PR and ACPA‐ PR had a moderate genetic correlation (0.38<R2<0.8).ConclusionThis study demonstrated the distinct genetic background of ACPA‐/+ PR patients. Additionally, our findings strengthened that PR and RA were not genetically similar.

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TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis

Gong

Wen

et al. 2019

Cancer Medicine

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The import of proteins into the nucleus plays an important role in tumor development. In addition to the classical nuclear import proteins importin‐β and importin‐α, there are many nonclassical nuclear import proteins that include TNPO2. The role of TNPO2 as a nonclassical nuclear import protein in tumors is limited. Our previous studies have shown that DYNC1I1 is a poor prognostic factor for gastric cancer and can promote the proliferation and metastasis of gastric cancer cells. An expression profile chip showed that TNPO2 was its potential downstream. DYNC1I1 upregulated TNPO2 expression by upregulating SP1, following which, SP1 recruited and bound to the P300‐acetylated TNPO2 promoter region histones, and thus promoted TNPO2 expression. At the same time, TNPO2 promoted gastric cancer cell proliferation and inhibited apoptosis by a mechanism that might be depending on the functional expression of P21.

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The cleavage of HuR interferes with its transportin-2-mediated nuclear import and promotes muscle fiber formation

Cited by 50 publications

References 30 publications

Apoptotic-induced cleavage shifts HuR from being a promoter of survival to an activator of caspase-mediated apoptosis

Apoptotic-induced cleavage shifts HuR from being a promoter of survival to an activator of caspase-mediated apoptosis

Identification of Distinct Genetic Profiles of Palindromic Rheumatism Using Whole‐Exome Sequencing

TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis

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