TBP-1 protects the human oncosuppressor p14ARF from proteasomal degradation.
The p14ARF tumor suppressor is a key regulator of cellular proliferation, frequently inactivated in human cancer. The mechanisms that regulate alternative reading frame (ARF) turnover have been obscure for long time, being ARF a relatively stable protein. Recently, it has been described that its degradation depends, at least in part, on the proteasome and that it can be subjected to N-terminal ubiquitination. We have previously reported that ARF protein levels are regulated by TBP-1 (Tat-Binding Protein 1), a multifunctional protein, component of the regulatory subunit of the proteasome, involved in different cellular processes. Here we demonstrate that the stabilization effect exerted by TBP-1 requires an intact N-terminal 39 amino acids in ARF and occurs independently from N-terminal ubiquitination of the protein. Furthermore, we observed that ARF can be degraded in vitro by the 20S proteasome, in the absence of ubiquitination and this effect can be counteracted by TBP-1. These observations seem relevant in the comprehension of the regulation of ARF metabolism as, among the plethora of cellular ARF's interactors already identified, only NPM/B23 and TBP-1 appear to be involved in the control of ARF intracellular levels.
Pollice
A
A
Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, Napoli, Italy.
Sepe
M
M
Villella
V R
VR
Tolino
F
F
Vivo
M
M
Calabrò
V
V
La Mantia
G
G
D000074183:ATPases Associated with Diverse Cellular Activities; D000595:Amino Acid Sequence / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D010455:Peptides; D025803:Tumor Suppressor Protein p14ARF; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; C064757:PSMC3 protein, human