Pro-proliferative function of the long isoform of PML-RARalpha involved in acute promyelocytic leukemia.
The promyelocytic leukemia (PML) gene codes for a tumor suppressor protein that is associated with distinct subnuclear macromolecular structures called the PML bodies. The PML gene is frequently involved in the t(15;17) chromosomal translocation of acute promyelocytic leukemia (APL). The translocation results in a fusion gene product, PML-RARalpha, in which the PML gene fuses to the retinoic acid receptor alpha (RARalpha) gene. PML-RARalpha has been shown to promote transcriptional repression of genes involved in myeloid terminal differentiation and to disrupt the architecture of PML bodies, a phenotype reversed by treatment with all trans retinoic acid (ATRA). However, there are several alternatively spliced isoforms of PML-RARalpha. Here, we addressed the differences between the short and the long isoforms of PML-RARalpha (L and S) since both are associated with APL. We demonstrate that PML-RARalphaL, but not PML-RARalphaS, can directly promote cell growth by transcriptionally activating the pro-proliferative gene, c-fos, in response to mitogenic stimulation. The activity of the PML-RARalphaL is completely sensitive to ATRA. We further show that this activation is not via direct recruitment of the protein to the c-fos promoter but indirectly by altering the chromosomal environment of the c-fos gene, thereby rendering it more accessible to the signal induced transcriptional activators. Our results suggest that in addition to antagonizing the PML-tumor suppressor or the PML-pro-apoptotic activity, PML-RARalpha proteins can also directly promote cell growth by activating c-fos.
Tussié-Luna
M I
MI
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Rozo
L
L
Roy
A L
AL
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000737:chemistry*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry*; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism; D000099186:Histone Deacetylase 3
D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D016760:Proto-Oncogene Proteins c-fos; D014212:Tretinoin; D000099186:Histone Deacetylase 3; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C484389:Hdac1 protein, mouse