c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells.
Burkitt's lymphoma (BL) is a highly malignant B-cell tumour characterized by chromosomal translocations that constitutively activate the c-myc oncogene. Here we show that BL cells are resistant to apoptosis and do not accumulate ubiquitin conjugates in response to otherwise toxic doses of inhibitors of the proteasome. Deubiquitinating enzymes and the cytosolic subtilisin-like protease tripeptidylpeptidase II are upregulated in BLs, and could be rapidly induced by the overexpression of c-myc in normal B cells carrying oestrogen-driven recombinant Epstein-Barr virus. Apoptosis was induced by inhibiting tripeptidylpeptidase II, suggesting that the activity of this protease may be required for the survival of BL cells. We thus show that there is a regulatory link between c-myc activation and changes in proteolysis that may affect malignant transformation.
Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden.
R
R
Gavioli
T
T
Frisan
S
S
Vertuani
G W
GW
Bornkamm
M G
MG
Masucci
D000626:Aminopeptidases; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D010450:Endopeptidases / Q000378:metabolism; D016259:Genes, myc; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D014452:Ubiquitins / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D009842:Oligopeptides; D011480:Protease Inhibitors; D011506:Proteins; D013450:Sulfones; D014452:Ubiquitins; C423405:tri-leucine-vinyl-sulfone; D004247:DNA; D010450:Endopeptidases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C091939:ubiquitin isopeptidase