Cellular uptake and localization of fluorescent derivatives of phorbol ester tumor promoters

Lamin B is rapidly phosphorylated in lymphocytes after activation of protein kinase C.

“…PKC has also been identified as the major cellular receptor for tumor-promoting phorbol esters, which activate PKC in a manner similar to diacylglycerol (3). Phorbol esters, when added to intact cells, rapidly partition into hydrophobic environments throughout the plasma membrane and cytoplasm (4), where they specifically bind and activate PKC (5,6). This cytoplasmic activation of PKC influences nuclear events, including the rapid transcription of specific sets of genes (7)(8)(9)(10).…”

“…The mechanisms through which these nuclear events are achieved are unknown. Because neither PKC nor phorbol esters apparently enter the nucleus (1,4), it has been postulated that the influence of phorbol esters upon transcription may result from indirect events, such as the phosphorylation of cytoplasmic proteins (4). Alternatively, protein kinase M (PKM), a proteolytic fragment of PKC that is known to be generated after phorbol treatment, may be translocated into nuclei to cause phosphorylation of nuclear proteins.…”

Artificial Analogs of Naturally Occurring Tumor Promoters as Biochemical Tools and Therapeutic Leads

“…In pioneering studies in 1985, Weinstein's and Tran's groups independently examined the intracellular localization of fluorescent analogs 11 and 12 respectively. 37,38) Both analogs were equipotent with TPA as PKC activators despite the difference in the position of the dansyl group in the side chain. Cellular uptake experiments using mouse embryo fibroblast C3H cells indicated that 11 and 12 entered cells rapidly and were distributed throughout the cytoplasm, but it was not clear whether the intracellular localization of the phorbol analogs reflected that of PKC.…”

“…Several biological evaluations indicated that 29 is a more potent tumor promoter than IL-V. Studies of 29 in uptake experiments using HeLa cells 54) showed that this fluorescent analog was distributed throughout the cytoplasm in the cells, similarly to the phorbol analogs (11 and 12). 37,38) Although no further cellular assays using 29 have been reported, it might be interesting to compare the localization pattern of 29 simultaneously with that of fluorescent PKC to determine whether PKC translocation by teleocidins is similar to that by phorbol esters. 39) Recently, new fluorescent IL-V analogs utilizing the indole ring have been developed.…”

Syntheses and Biological Activities of Photolabile Indolactam Derivatives; New Probes for the Receptor Analysis of Tumor Promoters

“…One of the major binding sites of these tumor promoters is said to be protein kinase C (PKC).2) However, recent studies on the cellular uptake of fluorescent derivatives of phorbol esters and teleocidins have indicated that not only the cell membrane but also the cytoplasm and nuclear membrane must be taken into account as putative receptor sites of these tumor promoters. 3 ) Recently, the existence of a tumor promoter-specific binding protein other than PKC in HL-60 cells has been demonstrated. 4 ) Direct identification of the receptor sites other than PKC is, therefore, indispensable to understand the pleiotropic effects of…”