MDM2-mediated degradation of p14ARF: a novel mechanism to control ARF levels in cancer cells.
We here show a new relationship between the human p14ARF oncosuppressor and the MDM2 oncoprotein. MDM2 overexpression in various cancer cell lines causes p14ARF reduction inducing its degradation through the proteasome. The effect does not require the ubiquitin ligase activity of MDM2 and preferentially occurs in the cytoplasm. Interestingly, treatment with inhibitors of the PKC (Protein Kinase C) pathway and use of p14ARF phosphorylation mutants indicate that ARF phosphorylation could play a role in MDM2 mediated ARF degradation reinforcing our previous observations that ARF phosphorylation influences its stability and biological activity. Our study uncovers a new potentially important mechanism through which ARF and MDM2 can counterbalance each other during the tumorigenic process.
Dipartimento di Biologia, Università di Napoli Federico II, Naples, Italy.
Maria
M
Vivo
Dipartimento di Biologia, Università di Napoli Federico II, Naples, Italy; Istituto di Genetica e Biofisica (IGB)-Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
Maria
M
Matarese
Dipartimento di Biologia, Università di Napoli Federico II, Naples, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche- Università di Napoli Federico II, Naples, Italy.
Maria
M
Sepe
Dipartimento di Biologia, Università di Napoli Federico II, Naples, Italy; Istituto di Biochimica delle Proteine (IBP)-Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
Rosaria
R
Di Martino
Dipartimento di Biologia, Università di Napoli Federico II, Naples, Italy; Diagnostica e Farmaceutica Molecolare- Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
Luisa
L
Festa
Dipartimento di Biologia, Università di Napoli Federico II, Naples, Italy.
Viola
V
Calabrò
Dipartimento di Biologia, Università di Napoli Federico II, Naples, Italy.
Girolama
G
La Mantia
Dipartimento di Biologia, Università di Napoli Federico II, Naples, Italy.
Alessandra
A
Pollice
D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm; D004789:Enzyme Activation; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*
D025803:Tumor Suppressor Protein p14ARF; D051736:Proto-Oncogene Proteins c-mdm2; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex