The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis.
Microphthalmia-associated transcription factor (MITF) M-form is a melanocyte-specific transcription factor that plays a key role in melanocyte development, survival, and differentiation. Here, we identified MITF as a new substrate of caspases and we characterized the cleavage site after Asp 345 in the C-terminal domain. We show that expression of a noncleavable form of MITF renders melanoma cells resistant to apoptotic stimuli, and we found that the C-terminal fragment generated upon caspase cleavage is endowed with a proapoptotic activity that sensitizes melanoma cells to death signals. The proapoptotic function gained by MITF following its processing by caspases provides a tissue-restricted means to modulate death in melanocyte and melanoma cells.
Larribere
Lionel
L
INSERM U597, Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée aux mélanomes, Ligue Nationale contre le Cancer, Equipe labellisée 2001, 06107 NICE Cedex 2, France.
Hilmi
Caroline
C
Khaled
Mehdi
M
Gaggioli
Cédric
C
Bille
Karine
K
Auberger
Patrick
P
Ortonne
Jean Paul
JP
Ballotti
Robert
R
Bertolotto
Corine
C
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; D020169:Caspases