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.
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: |
https://repository.cshl.edu/id/eprint/27370 |
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