RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins.
The RIG-G gene, originally isolated from an acute promyelocytic leukemia cell line NB4, codes for a 60-kDa cytoplasmic protein that is induced by all-trans retinoic acid (ATRA) treatment along with the induction of morphological differentiation of NB4 cells. Here, we provide evidence that ectopic expression of Rig-G in U937 cells can lead to a significant accumulation of cells at G(1)/S transition. Growth arrest seems to occur by modulating several major cell cycle regulatory players. Interestingly, Rig-G alters JAB1 cellular distribution through interacting with this protein and increases the intracellular level of p27 by preventing it from the JAB-1-dependent and ubiquitin/proteasome-mediated degradation. Furthermore, we demonstrate a role of Rig-G for c-myc down-regulation that results in an up-regulation of p21, tightly associated with cell cycle arrest. In addition, our studies reveal that Rig-G is a direct target of STAT1, a key transcription factor in regulating IFN responses, and may be one of the first experimentally proven molecular mediators for the antiproliferative effect of IFN-alpha. Considering that IFN-alpha and ATRA synergistically inhibit growth along the intracellular pathways triggered by the two compounds in many cell types, we suggest that Rig-G may also represent one of the key molecular nodes of signaling cross-talk between ATRA and IFN-alpha.
Xiao
Shu
S
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui Jin Hospital, Health Science Center, Chinese Academy of Sciences and School of Medicine, Shanghai Jiao Tong University, 197 Rui Jin Road II, Shanghai 200025, China.
Li
Dong
D
Zhu
Hai-Qing
HQ
Song
Man-Gen
MG
Pan
Xiao-Rong
XR
Jia
Pei-Min
PM
Peng
Lin-Ling
LL
Dou
Ai-Xia
AX
Chen
Guo-Qiang
GQ
Chen
Sai-Juan
SJ
Chen
Zhu
Z
Tong
Jian-Hua
JH
D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation
D050759:Cyclin-Dependent Kinase Inhibitor p21; C116468:IFIT3 protein, human; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007372:Interferons; D010447:Peptide Hydrolases