An oncogenic role for the phosphorylated h-subunit of human translation initiation factor eIF3.
Dysregulation of protein synthesis has been implicated in oncogenesis through a mechanism whereby "weak" mRNAs encoding proteins involved in cell proliferation are strongly translated when the protein synthesis apparatus is activated. Previous work has determined that many cancer cells contain high levels of eIF3h, a protein subunit of translation initiation factor eIF3, and overexpression of eIF3h malignantly transforms immortal NIH-3T3 cells. This is a general feature of eIF3h, as high levels also affect translation, proliferation, and a number of malignant phenotypes of CHO-K1 and HeLa cells and, most significantly, of a primary prostate cell line. Furthermore, overexpressed eIF3h inhibits Myc-dependent induction of apoptosis of primary prostate cells. eIF3h appears to function through translation, as the initial appearance of overexpressed eIF3h in rapidly induced NIH-3T3 cells correlates tightly with the stimulation of protein synthesis and the generation of malignant phenotypes. This oncogenic potential of eIF3h is enhanced by phosphorylation at Ser(183). Finally, reduction of eIF3h levels in breast and prostate cancer cell lines by short interfering RNA methods reduces their rates of proliferation and anchorage-independent growth in soft agar. The results provide compelling evidence that high eIF3h levels directly stimulate protein synthesis, resulting in the establishment and maintenance of the malignant state in cells.
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California-Davis, CA 95616, USA.
Lili
L
Zhang
Zeljka
Z
Smit-McBride
Xiaoyu
X
Pan
Jeanette
J
Rheinhardt
John W B
JW
Hershey
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016466:CHO Cells; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D039621:Eukaryotic Initiation Factor-3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics; D021122:Protein Subunits / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
D039621:Eukaryotic Initiation Factor-3; D021122:Protein Subunits; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering