wt p53 dependent expression of a membrane-associated isoform of adenylate kinase.
Six novel p53-inducible transcripts were recently cloned from Val5, a murine cell line stably expressing a temperature-sensitive p53 allele. One of the isolated clones represented a novel isoform of cytosolic adenylate kinase (AK1), a highly conserved monomeric enzyme involved in cellular homeostasis of adenine nucleotides. The corresponding protein, which we named AK1beta, was specifically induced upon activation of wt p53 in Val5 cells. The AK1beta protein differs from cytoplasmic AK1 by having 18 extra amino acids at the N-terminus. The extra residues in AK1beta provide a consensus signal for N-terminal myristoylation; as expected, AK1beta was shown to localize to the plasma membrane. The human AK1 gene contains several consensus p53 binding sites and we report that p53-dependent induction of the alternative AK1beta transcript also occurs in human cells. By using antisense ablation experiments in Val5 fibroblasts we show that AK1beta plays a relevant role in the establishment of reversible cell-cycle arrest as induced by p53 in these cells. These findings suggest that within a p53-dependent genetic program, a specific isoform of adenylate kinase has a previously undescribed growth-regulatory function, which might not necessarily require its best characterized biochemical activity.
Collavin
L
L
Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, AREA Science Park, Padriciano 99, 34012 Trieste, Italy.
Lazarevic
D
D
Utrera
R
R
Marzinotto
S
S
Monte
M
M
Schneider
C
C
D020413:3' Untranslated Regions; D016475:3T3 Cells; D000263:Adenylate Kinase / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D002462:Cell Membrane / Q000201:enzymology; D018076:DNA, Complementary; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D016372:RNA, Antisense; D012333:RNA, Messenger; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; D018076:DNA, Complementary; D007527:Isoenzymes; D008565:Membrane Proteins; D016372:RNA, Antisense; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000263:Adenylate Kinase