Translational control of protein kinase Ceta by two upstream open reading frames.
Protein kinase C (PKC) represents a family of serine/threonine kinases that play a central role in the regulation of cell growth, differentiation, and transformation. Posttranslational control of the PKC isoforms and their activation have been extensively studied; however, not much is known about their translational regulation. Here we report that the expression of one of the PKC isoforms, PKCeta, is regulated at the translational level both under normal growth conditions and during stress imposed by amino acid starvation, the latter causing a marked increase in its protein levels. The 5' untranslated region (5' UTR) of PKCeta is unusually long and GC rich, characteristic of many oncogenes and growth regulatory genes. We have identified two conserved upstream open reading frames (uORFs) in its 5' UTR and show their effect in suppressing the expression of PKCeta in MCF-7 growing cells. While the two uORFs function as repressive elements that maintain low basal levels of PKCeta in growing cells, they are required for its enhanced expression upon amino acid starvation. We show that the translational regulation during stress involves leaky scanning and is dependent on eIF-2alpha phosphorylation by GCN2. Our work further suggests that translational regulation could provide an additional level for controlling the expression of PKC family members, being more common than currently recognized.
Raveh-Amit
Hadas
H
Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Maissel
Adva
A
Poller
Jonathan
J
Marom
Liraz
L
Elroy-Stein
Orna
O
Shapira
Michal
M
Livneh
Etta
E
D020121:5' Untranslated Regions / Q000235:genetics; D000596:Amino Acids / Q000172:deficiency; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003062:Codon / Q000235:genetics; D017124:Conserved Sequence; D004790:Enzyme Induction; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics*; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D020121:5' Untranslated Regions; D000596:Amino Acids; D003062:Codon; D012333:RNA, Messenger; C081975:protein kinase C eta; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C