RGD Reference Report - SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling. - Rat Genome Database

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SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling.

Authors: Lin, Yu-Ching  Lu, Li-Ting  Chen, Hsin-Yi  Duan, Xueyan  Lin, Xia  Feng, Xin-Hua  Tang, Ming-Jer  Chen, Ruey-Hwa 
Citation: Lin YC, etal., Cancer Res. 2014 Dec 1;74(23):6935-46. doi: 10.1158/0008-5472.CAN-14-1330. Epub 2014 Oct 7.
RGD ID: 41404694
Pubmed: PMID:25293974   (View Abstract at PubMed)
DOI: DOI:10.1158/0008-5472.CAN-14-1330   (Journal Full-text)

The tumor-suppressor protein promyelocytic leukemia (PML) is aberrantly degraded in multiple types of human cancers through mechanisms that are incompletely understood. Here, we show that the phosphatase SCP1 and its isoforms SCP2/3 dephosphorylate PML at S518, thereby blocking PML ubiquitination and degradation mediated by the prolyl isomerase Pin1 and the ubiquitin ligase KLHL20. Clinically, SCP1 and SCP3 are downregulated in clear cell renal cell carcinoma (ccRCC) and these events correlated with PMLS518 phosphorylation, PML turnover, and high-grade tumors. Restoring SCP1-mediated PML stabilization not only inhibited malignant features of ccRCC, including proliferation, migration, invasion, tumor growth, and tumor angiogenesis, but also suppressed the mTOR-HIF pathway. Furthermore, blocking PML degradation in ccRCC by SCP1 overexpression or Pin1 inhibition enhanced the tumor-suppressive effects of the mTOR inhibitor temsirolimus. Taken together, our results define a novel pathway of PML degradation in ccRCC that involves SCP downregulation, revealing contributions of this pathway to ccRCC progression and offering a mechanistic rationale for combination therapies that jointly target PML degradation and mTOR inhibition for ccRCC treatment.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
clear cell renal cell carcinoma  IEP 41404694protein:decreased expression:kidney (human)RGD 
clear cell renal cell carcinoma  ISOPML (Homo sapiens)41404694; 41404694protein:decreased expression:kidney (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pml  (PML nuclear body scaffold)

Genes (Mus musculus)
Pml  (promyelocytic leukemia)

Genes (Homo sapiens)
PML  (PML nuclear body scaffold)


Additional Information