Segalla Simona, Rinaldi Laura, Kilstrup-Nielsen Charlotte, Badaracco Gianfranco, Minucci Saverio, Pelicci Pier Giuseppe, Landsberger Nicoletta
Dipartimento di Biologia Strutturale e Funzionale, Università dell'Insubria, 21052 Busto Arsizio (VA), Italy.
Mol Cell Biol. 2003 Dec;23(23):8795-808. doi: 10.1128/MCB.23.23.8795-8808.2003.
PML-RAR is an oncogenic transcription factor forming in acute promyelocytic leukemias (APL) because of a chromosomal translocation. Without its ligand, retinoic acid (RA), PML-RAR functions as a constitutive transcriptional repressor, abnormally associating with the corepressor-histone deacetylase complex and blocking hematopoietic differentiation. In the presence of pharmacological concentrations of RA, PML-RAR activates transcription and stimulates differentiation. Even though it has been suggested that chromatin alteration is important for APL onset, the PML-RAR effect on chromatin of target promoters has not been investigated. Taking advantage of the Xenopus oocyte system, we compared the wild-type transcription factor RARalpha with PML-RAR as both transcriptional regulators and chromatin structure modifiers. Without RA, we found that PML-RAR is a more potent transcriptional repressor that does not require the cofactor RXR and produces a closed chromatin configuration. Surprisingly, repression by PML-RAR occurs through a further pathway that is independent of nucleosome deposition and histone deacetylation. In the presence of RA, PML-RAR is a less efficient transcriptional activator that is unable to modify the DNA nucleoprotein structure. We propose that PML-RAR, aside from its ability to recruit aberrant quantities of histone deacetylase complexes, has acquired additional repressive mechanisms and lost important activating functions; the comprehension of these mechanisms might reveal novel targets for antileukemic intervention.
PML-RAR是一种致癌转录因子，在急性早幼粒细胞白血病（APL）中因染色体易位而形成。在没有其配体视黄酸（RA）的情况下，PML-RAR作为组成型转录抑制因子发挥作用，与共抑制因子-组蛋白脱乙酰酶复合物异常结合并阻断造血分化。在药理浓度的RA存在时，PML-RAR激活转录并刺激分化。尽管有人提出染色质改变对APL的发病很重要，但PML-RAR对靶启动子染色质的影响尚未得到研究。利用非洲爪蟾卵母细胞系统，我们将野生型转录因子RARα与PML-RAR作为转录调节因子和染色质结构修饰剂进行了比较。在没有RA的情况下，我们发现PML-RAR是一种更强效的转录抑制因子，它不需要辅因子RXR，并产生封闭的染色质构型。令人惊讶的是，PML-RAR的抑制作用通过一条独立于核小体沉积和组蛋白去乙酰化的进一步途径发生。在RA存在时，PML-RAR是一种效率较低的转录激活因子，无法修饰DNA核蛋白结构。我们提出，PML-RAR除了能够募集异常数量的组蛋白脱乙酰酶复合物外，还获得了额外的抑制机制并失去了重要的激活功能；对这些机制的理解可能揭示抗白血病干预的新靶点。
