scholarly journals Retinoic Acid Resistance at Late Stages of Human Papillomavirus Type 16-Mediated Transformation of Human Keratinocytes Arises Despite Intact Retinoid Signaling and Is Due to a Loss of Sensitivity to Transforming Growth Factor-β

Virology ◽  
2000 ◽  
Vol 270 (2) ◽  
pp. 397-407 ◽  
Author(s):  
Darrell R. Borger ◽  
Yi-de Mi ◽  
Gemma Geslani ◽  
Li Li Zyzak ◽  
Ayse Batova ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Human Papillomavirus ◽  
Transforming Growth Factor ◽  
Acid Resistance ◽  
Human Keratinocytes ◽  
Transforming Growth Factor Β ◽  
Retinoid Signaling ◽  
Human Papillomavirus Type 16 ◽  
Retinoic Acid Resistance ◽  
Late Stages

Constitutive Degradation of PML/RAR Through the Proteasome Pathway Mediates Retinoic Acid Resistance

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1477-1481 ◽  
Author(s):  
Mirco Fanelli ◽  
Saverio Minucci ◽  
Vania Gelmetti ◽  
Clara Nervi ◽  
Carlo Gambacorti-Passerini ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Proteasome Inhibitors ◽  
Acid Resistance ◽  
Parental Cell ◽  
Parental Cell Line ◽  
In Vitro Degradation ◽  
Nb4 Cells ◽  
Proteasome Pathway ◽  
Retinoic Acid Resistance

Abstract PML/RAR is the leukemogenetic protein of acute promyelocytic leukemia (APL). Treatment with retinoic acid (RA) induces degradation of PML/RAR, differentiation of leukaemic blasts, and disease remission. However, RA resistance arises during RA treatment of APL patients. To investigate the phenomenon of RA resistance in APL, we generated RA-resistant sublines from APL-derived NB4 cells. The NB4.007/6 RA-resistant subline does not express the PML/RAR protein, although its mRNA is detectable at levels comparable to those of the parental cell line. In vitro degradation assays showed that the half-life of PML/RAR is less than 30 minutes in NB4.007/6 and longer than 3 hours in NB4. Treatment of NB4.007/6 cells with the proteasome inhibitors LLnL and lactacystin partially restored PML/RAR protein expression and resulted in a partial release of the RA-resistant phenotype. Similarly, forced expression of PML/RAR, but not RAR, into the NB4/007.6 cells restored sensitivity to RA treatment to levels comparable to those of the NB4 cells. These results indicate that constitutive degradation of PML/RAR protein may lead to RA resistance and that PML/RAR expression is crucial to convey RA sensitivity to APL cells.

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