SIAH-1 promotes apoptosis and tumor suppression through a network involving the regulation of protein folding, unfolding, and trafficking: identification of common effectors with p53 and p21(Waf1).
We have previously described biological model systems for studying tumor suppression in which, by using H-1 parvovirus as a selective agent, cells with a strongly suppressed malignant phenotype (KS or US) were derived from malignant cell lines (K562 or U937). By using cDNA display on the K562/KS cells, 15 cDNAs were now isolated, corresponding to genes differentially regulated in tumor suppression. Of these, TSAP9 corresponds to a TCP-1 chaperonin, TSAP13 to a regulatory proteasome subunit, and TSAP21 to syntaxin 11, a vesicular trafficking molecule. The 15 cDNAs were used as a molecular fingerprint in different tumor-suppression models. We found that a similar pattern of differential regulation is shared by activation of p53, p21(Waf1), and the human homologue of Drosophila seven in absentia, SIAH-1. Because SIAH-1 is differentially expressed in the various models, we characterized it at the protein and functional levels. The 32-kDa, mainly nuclear protein encoded by SIAH-1, can induce apoptosis and promote tumor suppression. These results suggest the existence of a common mechanism of tumor suppression and apoptosis shared by p53, p21(Waf1), and SIAH-1 and involving regulation of the cellular machinery responsible for protein folding, unfolding, and trafficking.
Fondation Jean Dausset-CEPH (Human Polymorphism Study Center), 27 rue Juliette Dodu, 75010 Paris, France.
J P
JP
Roperch
F
F
Lethrone
S
S
Prieur
L
L
Piouffre
D
D
Israeli
M
M
Tuynder
M
M
Nemani
P
P
Pasturaud
M C
MC
Gendron
J
J
Dausset
M
M
Oren
R B
RB
Amson
A
A
Telerman
D000818:Animals; D017209:Apoptosis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004330:Drosophila / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D020014:K562 Cells; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017992:Parvovirus / Q000235:genetics; D017510:Protein Folding; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020298:U937 Cells; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins