Histone kinases cyclin-dependent kinase

The potential substrates for histone phosphorylation include N-terminal serine and threonine hydroxyl groups of H2A, H3, and H4 the N- and C-terminal tails of HI and the unique C-terminal of H2AX [19,29] (see Fig. 6). Similar to acetylation, phosphorylation appears to be a dynamic modification that transduces on/off signals to nuclear modulators. Enzymes implicated in regulating this pathway include the cyclin-dependent kinases and mitogen activated protein kinases, and the antagonistic phosphatase 1 [158,159]. 

Fig. 15.4 Brehm et al. and Magnaghi-Jaulin et al. have found that RB forms a complex with the E2F protein and the histone deacetylase HDACl. The complex represses expression of E2F-controlled promoters, such as the cydin E promoter. HDACl may facilitate the removal of h hly charged acetyl groups from core histones, causing a tighter association of DNA in nucleosomes, pieventiitg transcription factors (TFs) from gaining access to the DNA. The repression is then released in Gi in response to proliferative signals by phosphorylation of RB by cyclin-dependent kinases (Cdks). Phosphorylation dissociates RB from the complex, allowing transcription of E2FHresponsive promoters. (The information for this figure comes from Rg. 1 of ref. 27 with permission of the author and Nature.)...

Dai Y, Rahmani M, Grant S (2003a) An intact NF-kappaB pathway is required for histone deacetylase inhibitor-induced G1 arrest and maturation in U937 human myeloid leukemia cells. Cell Cycle 2 467-472 Dai Y, Rahmani M.Grant S (2003b) Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/ JNK- and NF-kappaB-dependent process. Oncogene 22 7108-7122... 

In addition to enzyme assays, HDAC inhibitors are usually evaluated in cancer cell lines, where they potently inhibit growth proliferation to provide a cell-based phenotypic readout of activity. The cellular potency of HDAC inhibitors can exceed their activity in enzyme assays, as the precise HDAC isoforms that drive proliferation in a given cell type may be unknown. In any case, growth inhibition data should be supplemented with evidence to confirm that it is due to HDAC inhibition and not off-target effects. Typically, confirmatory evidence involves Western blotting of client proteins such as histones for nuclear HDACs or tubulin for HDAC6 to detect an increase in acetylation levels, or changes in a downstream biomarker such as induction of the cyclin-dependent kinase inhibitor p21. 

Several examples of proteins involved in signal transduction pathways are reported to be encoded by auxin-induced mRNAs. These include the 3-subunit of a heterotrimeric G-protein (arcA) [105,106], cyclin-dependent protein kinases (cdc2s) [107-111], and calmodulin (PCM-1 and arCAM) [112,113]. Putative transcription factors are also represented in the list of auxin-induced mRNAs. Auxin-responsive cDNA clones for a G-box binding bZIP transcription factor (SGBF-1) [114] and a homeobox transcription factor (Athb-8) have been reported [115]. Another auxin-responsive mRNA, dbp, was proposed to be a lysine-rich nuclear protein similar to HI histone, and the recombinant protein was shown to bind nonspecilically to DNA [116]. The amino acid sequence of dbp is, however, highly similar (i.e., 67% identity and 80% similarity) to a potato plasma membrane-associated protein called remorin [117]. The remorin protein binds to both simple and complex galacturonides as well as DNA, but is not a nuclear protein in potato... 

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