The Transcription Coactivator Cbp Is a Dynamic Component of the Promyelocytic Leukemia Nuclear Body

Abstract

The transcription coactivator and histone acetyltransferase CAMP response element–binding protein (CBP) has been demonstrated to accumulate in promyelocytic leukemia (PML) bodies. We show that this accumulation is cell type specific. In cells where CBP does not normally accumulate in PML bodies, it can be induced to accumulate in PML bodies through overexpression of either CBP or Pml, but not Sp100. Using fluorescence recovery after photobleaching, we demonstrate that CBP moves rapidly into and out of PML bodies. In contrast, Pml and Sp100 are relatively immobile in the nucleoplasm and within PML nuclear bodies. They possess the characteristics expected of proteins that would play a structural role in the integrity of these subnuclear domains. Our results are consistent with CBP being a dynamic component of PML bodies and that the steady-state level in these structures can be modulated by Pml.

Re-expression of DNA methylation-silenced CD44 gene in a resistant NB4 cell line: rescue of CD44-dependent cell death by cAMP

“…[14][15][16] At present, little is known about the role of cAMP and its crosstalk with retinoids to induce the maturation and the apoptosis of APL. The mechanisms by which cAMP acts seem to be complex and may involve different signalling pathways and targets, including targeting transcription effectors, such as CREB, CBP300, PML-RARa or RXR receptors by direct or indirect phosphorylation, [18][19][20]49 or changes in nuclear bodies 17,50 or late and indirect re-expression of a large list of genes, 43,51,52 including c-Jun and CD44. Given the reported features shared by cAMP/retinoid (cell maturation) and cAMP/CD44 (cell death) cooperation, namely, the biological and biochemical effects are late and need a sustained signalling to develop, it is more clear that the mechanisms involved do not depend on a discrete set of cAMP/PKA targets, but rather result from a broad transcriptional reprogrammation of a multi-resistant tumour cell.…”

“…[14][15][16] The additional defects present in these resistant cells, as well as the molecular mechanism(s) by which cAMP acts to normalize the NB4-LR1 cell phenotype, are still poorly understood, although several proposals supported by independent investigations have been recently forwarded. [17][18][19][20][21] In this study, we demonstrate that there is an altered CD44 gene expression in the ATRA-maturation-resistant NB4-LR1 cells, and characterize the molecular defects behind this lack of CD44 receptor expression as DNA methylation of the CD44 promoter and deacetylation of histones at this locus. Importantly, full reactivation of CD44 gene transcription and synthesis of a functional CD44 receptor protein were rapidly obtained with a DNA methylating inhibitor (5-aza-CdR).…”

Transcriptional regulation in acute promyelocytic leukemia

“…In fact, many of the POD-associated proteins such as the HIPKs (Rochat-Steiner et al, 2000), Daxx (Charette et al, 2000), Sp100 (Sternsdorf et al, 1997b) and also PML itself (Stuurman et al, 1997), were detected outside of the PODs. Moreover, while it appears that there is little movement of PML between the PODs and the nucleoplasm, CBP has been shown to be a dynamic component of the PODs (Boisvert et al, 2000(Boisvert et al, , 2001. The presence of CBP and other transcription factors suggests that the PODs may serve either as storage sites or act as staging areas where transcription factors may be assembled and/or modi®ed.…”

PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage

“…The precise function of NBs remains unclear. The presence of proteins such as DAXX, CREB binding protein (CBP), Bloom (BLM) and p53 within these structures (Everett et al, 1999;Boisvert et al, 2001;Ishov et al, 1999;Pearson et al, 2000;Fogal et al, 2000;Zhong et al, 1999Zhong et al, , 2000, imply that they may exert multiple roles in the cellular stress response. In agreement, PML NBs are dynamic structures that are modi®ed in response to a variety of stresses including heat shock (Maul et al, 1995), arsenic (Zhu et al, 1997;Muller et al, 1998) and oncogenes (Pearson et al, 2000;Ferbeyre et al, 2000).…”