Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization
Authors: S Cuvellier
T Rivera Vargas
A Polesskaya
S Boudoukha
G Pinna
M Souidi
A Simon
Journal: Oncogene (2014)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: RNA-binding proteins; IMP family; IMP-3; gene expression; cancer
Affiliations: 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France., 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France [4] Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA., Inserm U1016, Institut Cochin, Département Génétique et Développement, Paris, France.

Abstract:  RNA-binding proteins of the IMP family (insulin-like growth factor 2 (IGF2) mRNA-binding proteins 1-3) are important post-transcriptional regulators of gene expression. Multiple studies have linked high expression of IMP proteins, and especially of IMP-3, to an unfavorable prognosis in numerous types of cancer. The specific importance of IMP-3 for cancer transformation remains poorly understood. We here show that all three IMPs can directly bind the mRNAs of cyclins D1, D3 and G1 (CCND1, D3 and G1) in vivo and in vitro, and yet only IMP-3 regulates the expression of these cyclins in a significant manner in six human cancer cell lines of different origins. In the absence of IMP-3, the levels of CCND1, D3 and G1 proteins fall dramatically, and the cells accumulate in the G1 phase of the cell cycle, leading to almost complete proliferation arrest. Our results show that, compared with IMP-1 and IMP-2, IMP-3 is enriched in the nucleus, where it binds the transcripts of CCND1, D3 and G1. The nuclear localization of IMP-3 depends on its protein partner HNRNPM and is indispensable for the post-transcriptional regulation of expression of the cyclins. Cytoplasmic retention of IMP-3 and HNRNPM in human cancer cells leads to significant drop in proliferation. In conclusion, a nuclear IMP-3-HNRNPM complex is important for the efficient synthesis of CCND1, D3 and G1 and for the proliferation of human cancer cells. 

Retracted: No

PubPeer comments:
 Figure 1a. Much more similar than expected. https: imgur.com n5m0Grp , 
 Figure 2d. Much more similar than expected. https: imgur.com 5QfemkJ , 
 #1 Dear Pub Peer, Here is a scan of the original lab journal of the student who had performed this western blot, with all the details of the experiment. I will be happy to have anyone examine this journal. Best regards, Anna Polesskaya ![file] , 
 #1 I agree with your concerns, although I m not sure about the CCNG1, and I think there s a possible repeat in the IMP-2 band. Here s a false color image I created to study the image. *** ![file] , 
 #2 Here is a false color image of that portion of Figure 2. *** ![file] , 
 #2 Dear Pub Peer, I just found the original experiment. Probably, the image got stretched because we only took the bottom part of the panel (to avoid confusion because of the clearly non-specific upper band). But these two lanes do look very similar. I have not noticed it before, and will look in this matter. Best regards, Anna Polesskaya ![file] , 
 Figure 1b. https: imgur.com T6wzmnf , 
 #4  I think there s a possible repeat in the IMP-2 band . https: imgur.com 77Qq7nX , 
 #8 Does the author have an update? ,