Enforced expression of PPP1R13L increases tumorigenesis and invasion through p53-dependent and p53-independent mechanisms

Laska, M. J., Lowe, S. W., Zender, L., Hearn, S. A., Vogel, U., Jensen, U. B., Bric, A., Nexo, B. A. (September 2009) Enforced expression of PPP1R13L increases tumorigenesis and invasion through p53-dependent and p53-independent mechanisms. Mol Carcinog, 48 (9). pp. 832-42.

URL: http://www.ncbi.nlm.nih.gov/pubmed/19263435
DOI: 10.1002/mc.20528

Abstract

PPP1R13L was initially identified as a protein that binds to the NF-kappaB subunit p65/RelA and inhibits its transcriptional activity. It also binds p53 and inhibits its action. One set of experimental findings based on overexpression of PPP1R13L indicates that PPP1R13L blocks apoptosis. Another set of experiments, based on endogenous production of PPP1R13L, suggests that the protein may sometimes be pro-apoptotic. We have used primary mouse embryonic fibroblasts (MEFs), dually transformed by HRAS and adenovirus E1A and differing in their p53 status, to explore the effects of PPP1R13L overexpression, thus examining the ability of PPP1R13L to act as an oncoprotein. We found that overexpression of PPP1R13L strongly accelerated tumor formation by RAS/E1A. PPP1R13L overexpressing cells were depleted for both p53 and active p65/RelA and we found that both p53-dependent and -independent apoptosis pathways were modulated by PPP1R13L. Finally, studies with the proteasome inhibitor MG132 revealed that overexpression of PPP1R13L causes faster p53 degradation, a likely explanation for the depletion of p53. Taken together, our results show that increased levels of PPP1R13L can increase tumorigenesis and furthermore suggest that PPP1R13L can influence metastasis.

Item Type: Paper
Uncontrolled Keywords: Adenovirus E1A Proteins/genetics/metabolism Animals Apoptosis Cell Cycle/genetics/physiology Cell Movement/genetics/physiology Cell Proliferation Cell Transformation, Neoplastic/genetics Embryo, Mammalian/cytology Fibroblasts/cytology/drug effects/metabolism Intracellular Signaling Peptides and Proteins/genetics/*metabolism Leupeptins/pharmacology Mice Mice, Knockout Mice, Nude Neoplasm Invasiveness Neoplasms, Experimental/genetics/metabolism/*pathology Repressor Proteins/genetics/*metabolism Signal Transduction/genetics/physiology Transcription Factor RelA/genetics/metabolism Transfection Tumor Suppressor Protein p53/genetics/*metabolism ras Proteins/genetics/metabolism
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: September 2009
Date Deposited: 21 Feb 2013 16:10
Last Modified: 21 Feb 2013 16:10
PMCID: PMC3328301
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27370

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