Identification of distinctive patterns of USP19-mediated growth regulation in normal and malignant cells.
We previously reported that the USP19 deubiquitinating enzyme positively regulates proliferation in fibroblasts by stabilizing KPC1, a ubiquitin ligase for p27(Kip1). To explore whether this role of USP19 extends to other cellular systems, we tested the effects of silencing of USP19 in several human prostate and breast models, including carcinoma cell lines. Depletion of USP19 inhibited proliferation in prostate cancer DU145, PC-3 and 22RV1 cells, which was similar to the pattern established in fibroblasts in that it was due to decreased progression from G1 to S phase and associated with a stabilization of the cyclin-dependent kinase inhibitor p27(Kip1). However, in contrast to previous findings in fibroblasts, the stabilization of p27(Kip1) upon USP19 depletion was not associated with changes in the levels of the KPC1 ligase. USP19 could also regulate the growth of immortalized MCF10A breast epithelial cells through a similar mechanism. This regulatory pattern was lost, though, in breast cancer MCF7 and MDA-MB-231 cells and in prostate carcinoma LNCaP cells. Of interest, the transformation of fibroblasts through overexpression of an oncogenic form of Ras disrupted the USP19-mediated regulation of cell growth and of levels of p27(Kip1) and KPC1. Thus, the cell context appears determinant for the ability of USP19 to regulate cell proliferation and p27(Kip1) levels. This may occur through both KPC1 dependent and independent mechanisms. Moreover, a complete loss of USP19 function on cell growth may arise as a result of oncogenic transformation of cells.
Polypeptide Laboratory, Department of Medicine, McGill University Health Centre Research Institute, McGill University, Montreal, Quebec, Canada.
Yu
Y
Lu
Nathalie
N
Bedard
Simone
S
Chevalier
Simon S
SS
Wing
D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis*; D010450:Endopeptidases / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000032:analysis
D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C559917:USP19 protein, human
Chem Rev. 2009 Apr;109(4):1495-508
19243136
Cell. 1996 May 31;85(5):707-20
8646779
Genes Dev. 1999 Jun 15;13(12):1501-12
10385618
J Biol Chem. 2005 May 6;280(18):17694-700
15746103
Cancer Res. 2006 Sep 1;66(17):8625-32
16951176
Mol Cell Biol. 2006 Aug;26(16):5994-6004
16880511
Cell. 1996 May 31;85(5):733-44
8646781
Nat Cell Biol. 1999 Aug;1(4):193-9
10559916
Cancer Res. 2007 Nov 15;67(22):10789-95
18006823
Nat Cell Biol. 2004 Dec;6(12):1229-35
15531880
Science. 1995 Aug 4;269(5224):682-5
7624798
Mol Cell Biol. 2005 Nov;25(21):9292-303
16227581
Cell. 2009 Jul 23;138(2):389-403
19615732
Nat Genet. 2000 Jun;25(2):160-5
10835629
Annu Rev Biochem. 2001;70:503-33
11395416
Nature. 1995 Mar 9;374(6518):131-4
7877684
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):811-6
14711987
Cell. 2005 Dec 2;123(5):773-86
16325574
Cell. 1996 May 31;85(5):721-32
8646780
Cancer Sci. 2009 May;100(5):866-72
19445020
Curr Biol. 1999 Jun 17;9(12):661-4
10375532
Cancer Res. 2010 Apr 15;70(8):3329-39
20388806
Mol Cell Biol. 2009 Jan;29(2):547-58
19015242
J Cell Mol Med. 2010 Apr;14(4):944-53
19298520
Trends Biochem Sci. 2005 Nov;30(11):630-41
16236519
Nat Rev Cancer. 2008 Apr;8(4):253-67
18354415