In acute promyelocytic leukemia (APL), the typical t(15;17) and the rare t(11;17) translocations express, respectively, the PML͞RAR␣ and PLZF͞RAR␣ fusion proteins (where RAR␣ is retinoic acid receptor ␣). Herein, we demonstrate that the PLZF and PML proteins interact with each other and colocalize onto nuclear bodies (NBs). Furthermore, induction of PML expression by interferons leads to a recruitment of PLZF onto NBs without increase in the levels of the PLZF protein. PML͞RAR␣ and PLZF͞RAR␣ localize to the same microspeckled nuclear domains that appear to be common targets for the two fusion proteins in APL. Although PLZF͞RAR␣ does not affect the localization of PML, PML͞ RAR␣ delocalizes the endogenous PLZF protein in t(15;17)-positive NB4 cells, pointing to a hierarchy in the nuclear targeting of these proteins. Thus, our results unify the molecular pathogenesis of APL with at least two different RAR␣ gene translocations and stress the importance of alterations of PLZF and RAR␣ nuclear localizations in this disease.Acute promyelocytic leukemia (APL) represents approximately 10% of all adult acute myeloid leukemias (1). The molecular pathogenesis of APL is, at least in part, associated with the disruption of the retinoic acid receptor ␣ (RAR␣) gene through its fusion to one of four different loci (2-7). These translocations result in the expression of chimeric RAR␣ fusion proteins that retain the DNA and ligand binding domains of the receptor and gain a dimerization domain from the fusion partner. Paradoxically, APL is the first human malignancy that may undergo complete remission in response to differentiation therapy with all-trans-retinoic acid (RA). The molecular basis of these remissions is still disputed.The majority of APL cases, and all cases that consistently respond to RA treatment, possess the t(15;17) translocation that fuses the PML and RAR␣ genes (3,(8)(9)(10)(11)(12). PML is a member of a functionally diverse gene family that encodes proteins characterized by the presence of a N-terminal C 3 HC 4 RING-finger motif (13), followed by one or two cysteine-rich regions (B boxes) and a coiled-coil protein dimerization interface. The function of PML is unknown, but up-regulation of its expression by interferons (IFNs) (14-16) and its negative effect on cell growth and cellular transformation by cooperating oncogenes (17-19) suggest a role in growth control. The product of the wild-type PML gene is a phosphoprotein (20) that localizes both in the nucleoplasm and in the specific multiprotein structures called PML nuclear bodies (NBs) (20-24). The PML͞RAR␣ fusion protein, which is expressed in APL cells as a result of t(15;17), contains all predicted PML structural motifs and is able to delocalize the wild-type PML and other NB components onto discrete microspeckled nuclear structures (21-24). It is still unclear which role, if any, disruption of NBs and͞or establishment of microspeckled structures play in cellular transformation. Nevertheless, complete restoration of NBs upon RA treatment in NB4 ...
A comprehensive study is presented for the influence of misfit strain, adhesion strength, and lattice symmetry on the complex Moiré patterns that form in ultrathin films of honeycomb symmetry adsorbed on compact triangular or honeycomb substrates. The method used is based on a complex Ginzburg-Landau model of the film that incorporates elastic strain energy and dislocations. The results indicate that different symmetries of the heteroepitaxial systems lead to distinct types of domain wall networks and phase transitions among various surface Moiré patterns and superstructures. More specifically, the results show a dramatic difference between the phase diagrams that emerge when a honeycomb film is adsorbed on substrates of honeycomb versus triangular symmetry. It is also shown that in the small deformation limit, the complex Ginzburg-Landau model reduces to a two-dimensional sine-Gordon free energy form. This free energy can be solved exactly for one dimensional patterns and reveals the role of domains walls and their crossings in determining the nature of the phase diagrams.
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