A novel RCE1 isoform is required for H-Ras plasma membrane localization and is regulated by USP17

Jaworski, Jakub; Govender, Ureshnie; McFarlane, Cheryl; Vega, Michelle de la; Greene, Michelle K.; Rawlings, Neil D.; Johnston, James A.; Scott, Christopher J.; Burrows, James F.

doi:10.1042/bj20131213

Cited by 13 publications

(18 citation statements)

References 28 publications

(34 reference statements)

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“…However, the results were unexpected. Although the literature has reported that RCE1 is important for the activation of the Ras oncogene [10], our results suggested that RCE1 had an anti-tumor role in CRC. We found that the RCE1 expression levels were negatively correlated with the prognosis of CRC patients.…”

Section: Discussioncontrasting

confidence: 70%

“…Increasing evidence suggests that RCE1 is required for Ras activation [9, 10]. Abnormal activation of Ras is important in CRC development, and there have been many drugs that either have targeted the Ras signaling pathway or were affected by Ras activation [11, 18].…”

Section: Discussionmentioning

confidence: 99%

“…Acculumulating evidence suggests that RCE1 plays an important role in cancer development [8]. Moreover, it has been reported that RCE1 was required for membrane localization and activation of Ras [9, 10]. It is well known that Ras mutations and abnormal activation contribute to the development of several types of cancer, including CRC [11].…”

Section: Introductionmentioning

confidence: 99%

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Reduced RCE1 expression predicts poor prognosis of colorectal carcinoma

et al. 2017

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BackgroundAs an end-proteolytic enzyme that cleaves the last three residues of proteins with a terminal CAAX, Ras-converting enzyme 1 (RCE1) has an essential role in multiple signaling pathways and take part in the process of differentiation, proliferation and carcinogenesis. The aim of the study is to investigate expression pattern of RCE1 and its prognosis in colorectal carcinoma (CRC).MethodsThe expression of RCE1 and phospho-MAPK family members was confirmed by immunohistochemical staining of CRC tissues. miR-RCE1 lentiviral vectors were transduced into HCT116 and SW489 cells. Reverse transcription PCR (RT-PCR) and western blot were conducted to measure the transfection efficiency. Transwell assays were used to detect the invasiveness of CRC cells.ResultsIn the present study, we assessed RCE1 expression in 244 CRC specimens and matching adjacent, non-tumorous tissues by immunohistochemistry (IHC). Compared with the matched adjacent non-tumor tissue samples, the RCE1 reduced in the tumor tissue samples (p < 0.001). RCE1 expression was significantly decreased in 106 of 244 (43.4%) CRC cases. In univariate and multivariate analyses, Decreasing expression of RCE1 independently predicts poor prognosis for patients in both overall survival and disease-free survival. Further study indicated that RCE1 influenced tumor invasion through the p38 pathway. Knockdown of RCE1 reduced phosphorylation and significantly increased the invasive capacity of CRC cells.ConclusionTaken together, the outcomes of this study indicate that RCE1 acts as a tumor suppressor in CRC, as its reduced expression may increase CRC cell invasion and independently predict an unsatisfactory prognosis in CRC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3393-3) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reduced RCE1 expression predicts poor prognosis of colorectal carcinoma

et al. 2017

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“…In the presence of active USP17, deubiquitination occurs, causing this isoform to leave the ER and be degraded. As a result of this degradation, CaaX modification is blocked [136]. Research in this area could lead to another potential alternative for targeting Ras.…”

Section: Introductionmentioning

confidence: 99%

How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization

Brock

Reiners

et al. 2016

MRMC

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Oncogenic Ras proteins are a driving force in a significant set of human cancers and wild-type, unmutated Ras proteins likely contribute to the malignant phenotype of many more. The overall challenge of targeting activated Ras proteins has great promise to treat cancer, but this goal has yet to be achieved. Significant efforts and resources have been committed to inhibiting Ras, but these energies have so far made little impact in the clinic. Direct attempts to target activated Ras proteins have faced many obstacles, including the fundamental nature of the gain-of-function oncogenic activity being produced by a loss-of-function at the biochemical level. Nevertheless, there has been very promising recent pre-clinical progress. The major strategy that has so far reached the clinic aimed to inhibit activated Ras indirectly through blocking its post-translational modification and inducing its mislocalization. While these efforts to indirectly target Ras through inhibition of farnesyl transferase (FTase) were rationally designed, this strategy suffered from insufficient attention to the distinctions between the isoforms of Ras. This led to subsequent failures in large-scale clinical trials targeting K-Ras driven lung, colon, and pancreatic cancers. Despite these setbacks, efforts to indirectly target activated Ras through inducing its mislocalization have persisted. It is plausible that FTase inhibitors may still have some utility in the clinic, perhaps in combination with statins or other agents. Alternative approaches for inducing mislocalization of Ras through disruption of its palmitoylation cycle or interaction with chaperone proteins are in early stages of development.

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“…In numerous cancer phenotypes, expression of USP17 is upregulated, resulting in its expression outside of these checkpoints which causes an excess of stabilized CDC25A that applies stress to the cellcycle resulting in unregulated cancer cell proliferation ( Figure 1B) [5][6][7]. Other identified substrates of USP17 include the Ras converting enzyme 1 (RCE1) and the histone deacetylase dependent Sin3A co-repressor complex component, SDS3, both of which also play a role in cell-cycle regulation [8][9][10].…”

Section: Introductionmentioning

confidence: 99%