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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here that the negative cell cycle regulator protein p53 is an in vivo and in vitro substrate for protein kinase C, a cellular receptor for the tumor-promoter phorbol esters. We also demonstrate that p53 interacts in a calcium-dependent manner with S100b, a member of the S100 protein family involved in cell cycle progression and cell differentiation, and that such an interaction inhibits in vitro p53 phosphorylation by protein kinase C. The interaction between p53 and S100b was utilized for the purification of cellular and recombinant murine p53 by affinity chromatography with S100b-Sepharose. Furthermore, and of particular interest, we have shown that purified p53 undergoes temperature-dependent oligomerization and that the interaction between S100b and p53 not only induces total inhibition of p53 oligomerization but also promotes disassembly of the p53 oligomers. We suggest that these effects result from the binding of S100b to the multifunctional basic C-terminal domain of p53 and propose that p53 may be a cellular target for the S100 protein family members involved in the control of the cell cycle at the G0-G1/S boundary.
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PMID:Characterization of the tumor suppressor protein p53 as a protein kinase C substrate and a S100b-binding protein. 145 55

The myeloid interleukin-3 (IL-3) dependent cell line, FDC-P1, enters the G0 stage of the cell cycle after IL-3 deprivation for 24 hr. The expression of 13 protooncogenes and immediate-early genes was compared with 4 "control" genes after the addition of either IL-3 or phorbol myristate acetate (PMA) to IL-3-deprived cells. mRNA transcripts encoding c-myc and the T-cell receptor c-gamma gene were induced to high levels only after IL-3 addition, whereas c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 were induced transiently only after PMA addition. The remaining genes (fra-1, p53, jun-D, c-Ha-ras, c-Ki-ras, c-raf, beta-actin, ornithine decarboxylase, and histone 2B) were detected after culture with either IL-3 or PMA. When cells were serum- and IL-3-deprived, c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 were detected after exposure to either serum or PMA. Moreover, culture with cycloheximide and PMA resulted in superinduction of these genes, whereas cycloheximide and IL-3 addition did not. mRNAs encoding these genes had half-lives of 10-20 min after PMA treatment, whereas that of beta-actin was longer (greater than 2 hr), suggesting that short mRNA half-lives contributed to the transient nature of these genes. Although c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 expression can be detected in IL-3-dependent cells after exposure to either PMA or serum, these genes were not detected after IL-3 addition, which allows cell-cycle progression. These results document the existence of IL-3 and PMA-responsive genes and demonstrate that IL-3 and protein kinase C agonists can induce distinct patterns of gene expression.
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PMID:Interleukin-3 and phorbol esters induce different patterns of immediate-early gene expression in an interleukin-3 dependent cell line. 170 18

CR1 (C3b receptor) and CR2 (C3d/EBV receptor) are two C3 receptors expressed on B lymphocytes. CR1 and CR2 have structural similarities and their cross-linking at the B cell surface by antibodies or specific ligands in multimeric forms induce B cell activation. However, activation of human B cells through cell surface interactions or by intracellular protein kinase C activators leads to phosphorylation of CR2 but not CR1. CR2 is phosphorylated on serine and tyrosine residues. Analysis of post-membrane events associated with CR2 revealed intracellular interactions of CR2 with p53, a plasma membrane anti-oncogene-encoded phosphoprotein, and with p120, a nuclear phosphoribonucleoprotein. These intracellular interactions probably represent important steps in the signalling functions of CR2.
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PMID:Structure and signalling functions of C3 receptors on human B cells. 215

Hexamethylene bisacetamide (HMBA) is a most effective compound as an inducer of MELC differentiation. HMBA-mediated terminal differentiation of MELC is a multistep process. There is a latent period during which a number of changes occur including the appearance of Ca2+ and phospholipid independent PKC activity in the cytosol, and modulation in expression of several genes, including c-myc, c-myb, c-fos and the p53 genes. During this latent period there is neither detectable commitment to terminal differentiation (including terminal cell division) or increased transcription of the globin genes. HMBA-mediated commitment to terminal differentiation is first detected at about 12 hr and increases in a stochastic fashion, until over 95% of the population has been recruited to terminal differentiation by 48 to 60 hr. Commitment is associated with persistent HMBA-mediated suppression of c-myb gene expression. By 36 to 48 hr, transcription of the globin genes has increased by 10 to 30 fold, whereas transcription of rRNA genes is suppressed. The steroid, dexamethasone, and the tumor promotor, phorbol-12-myristate-13-acetate, suppress HMBA-induced MEL cell terminal differentiation. The evidence indicates that these agents act at a late step during the latent period. Recently, we showed that MELC variants selected for resistance to vincristine have a marked increased sensitivity to HMBA. Compared to the parental MELC strains, vincristine resistant MELC are: A) responsive to 1/5 to 1/10 the concentration of HMBA; B) induced to terminal differentiation without a latent period and C) resistant to inhibition of HMBA induced terminal differentiation by dexamethasone or tumor promotor. The vincristine resistant MELC have characteristics of the multidrug resistant phenotype. A number of independently derived vincristine resistant MELC lines show similar altered response to HMBA. These findings suggest that vincristine resistance leads to a constitutive expression of a factor or factors induced by HMBA in vincristine sensitive (wild type) MELC during the latent period and which are essential to the transition to terminal differentiation.
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PMID:Induced differentiation of murine erythroleukemia cells (MELC) by polar compounds: marked increased sensitivity of vincristine resistant MELC. 261 74

Hexamethylene bisacetamide (HMBA), a highly polar compound, induces murine erythroleukemia (MEL) cells to express the erythroid phenotype, including cessation of proliferation. Inducer-mediated differentiation of MEL (DS19) cells is a multistep process characterized by a latent period during which a number of changes occur including alterations in ion flux, an increase in membrane-bound protein kinase C (PKC) activity, the appearance of Ca2+ and phospholipid-independent PKC activity in the cytosol, and modulation in expression of a number of genes such as c-myc, c-myb, c-fos and the p53 genes. HMBA-mediated commitment to terminal differentiation is first detected at about 12 hours and increases in a stochastic fashion until over 95% of the population is recruited to terminal differentiation by 48 to 60 hours. Commitment is associated with persistent suppression of c-myb gene expression. By 36 to 48 hours, transcription of the globin genes has increased 10 to 30 fold, whereas transcription from rRNA genes is suppressed. The steroid, dexamethasone, or the tumor promoter, phorbol-12-myristate-13-acetate (TPA), suppress HMBA-induced MEL cell terminal differentiation. These agents appear to act at a late step during the latent period. MEL cell lines derived from DS19 by selection for resistance to vincristine are: 1) induced to commit without a detectable latent period, 2) markedly more sensitive to HMBA, and 3) resistant to dexamethasone or TPA inhibition of HMBA-induced commitment. The data suggests that vincristine-resistant MEL cells express a factor which circumvents essential HMBA-mediated early events. In vitro studies with HMBA provide a basis for the application of HMBA to clinical therapy of human cancers. Clinical trials with HMBA have been initiated.
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PMID:Hexamethylene bisacetamide-induced differentiation of transformed cells: molecular and cellular effects and therapeutic application. 304 66

The human ets-2 gene is a homolog of the v-ets oncogene of the E26 virus and codes for a 56-kilodalton nuclear protein. The ets-2 protein is phosphorylated and has a rapid turnover, with a half-life of 20 min. When human lymphocytic CEM cells were treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), the level of the ets-2 protein was quickly elevated 5- to 20-fold. This effect of TPA was mimicked by a synthetic diacylglycerol, 1-oleoyl-2-acetyl glycerol, and was blocked by the protein kinase C inhibitor H7, indicating that protein kinase C is involved in the induction. The increase in the ets-2 protein was due to stabilization of the protein, because the protein had a half-life of more than 2 h in the presence of TPA and the ets-2 mRNA level did not increase significantly upon TPA treatment. The protein synthesis inhibitor cycloheximide enhanced the effect of TPA on the ets-2 protein and could itself slow turnover of the protein. Properties of the ets-2 protein, such as nuclear localization, phosphorylation, rapid turnover, and response to protein kinase C, indicate that this protein belongs to a group of oncogene proteins which are generally thought to have regulatory functions in the nucleus (e.g., myc, fos, myb, and p53). Our results suggest that protein kinase C, either directly or indirectly, regulates the level of the ets-2 protein by posttranslational mechanisms.
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PMID:A short-lived nuclear phosphoprotein encoded by the human ets-2 proto-oncogene is stabilized by activation of protein kinase C. 306 67

MELC may be induced to terminal erythroid differentiation by HMBA and other agents. Although the mechanism is not known, changes in cell function and gene expression can be identified during an early "latent" period, prior to commitment to terminal differentiation. These include a decrease in diacylglycerol concentration and in Ca+2 and phospholipid-dependent protein kinase C activity, accompanied by suppression of c-myb and c-myc gene transcription, a fall in p53 protein, and an increase in c-fos mRNA. Commitment is first detected by 12 hours and is associated with persistent suppression of c-myb gene transcription. Transcription of the erythroid-specific genes, alpha 1 and beta maj globin, is increased 10- to 30-fold, whereas synthesis of rRNA is suppressed, and there is activation or suppression of a number of additional genes that remain to be characterized. The potential regulatory roles of changes in protein kinase C activity and in proto-oncogene expression in initiating and sustaining the process of differentiation also remain to be elucidated.
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PMID:Induced erythroleukemia differentiation: cellular and molecular aspects. 331 Dec 22

HMBA induces MEL cells to terminal erythroid differentiation. HMBA causes a decrease in diacylglycerol concentration, a decrease in Ca+2 and phospholipid-dependent protein kinase C activity (within 2 hr). There is an early (within 1-2 hrs) suppression of c-myb and c-myc gene transcription and an increase in c-fos mRNA (within 4 hrs). During the early or "latent" period there is no detectable commitment of MELC to terminal cell division or expression of differentiated genes such as alpha 1 or beta maj globin genes. HMBA-induced commitment to terminal differentiation is detected by 12 hrs and over 95% become committed cells by 48-60 hrs. Commitment is associated with persistent suppression of c-myb gene transcription and elevated levels of c-fos mRNA, whereas the level of c-myc mRNA returns to that of uninduced cells. By 36-48 hrs, transcription of the alpha 1 and beta maj globin genes increases 10-30 fold, and that of rRNA genes is suppressed. Changes in expression of c-myb, c-myc, c-fos and p53 genes that occur early during HMBA-induced differentiation may be important in the multistep process involved in commitment of MEL cells to terminal differentiation. Continued suppression of c-myb gene expression may be required for terminal differentiation of these cells.
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PMID:Induction of transformed cells to terminal differentiation. 332 66

HMBA induces MELC to terminal erythroid differentiation. The mechanism of HMBA action is not known. Culture with HMBA causes changes in gene expression which occur during the early "latent period", that is, prior to commitment to terminal differentiation. The inducer causes a decrease in diacylglycerol concentration, a decrease in Ca+2 and a decrease in phospholipid-dependent protein kinase C activity (within 2 hr) (Figure 2). There is an early suppression (within 1-2 hrs) of c-myb and c-myc gene transcription and an increase in c-fos mRNA (within 4 hrs). HMBA-induced commitment to terminal differentiation is detected by 12 hrs and over 95% become committed cells by 48 to 60 hrs. Commitment is associated with persistent suppression of c-myb gene transcription and elevated levels of c-fos mRNA whereas the level of c-myc mRNA returns to that of uninduced cells. By 36 to 48 hrs, transcription of alpha 1 and beta maj globin genes is increased 10 to 30 fold, while that of rRNA genes is suppressed. It is not yet clear how the protein products of proto-oncogenes elicit or modify cellular responses. Changes in expression of c-myb, c-myc, c-fos and p53 genes which occur during HMBA-induced differentiation, as well as in several other systems, suggest that products of these genes may have a role in regulating expression of multiple genes. One possible application of the established pattern of HMBA-induced modulation of gene expression during MELC differentiation may be in following the effects of cyto-differentiation agents during treatment of cancers. Phase I and Phase II chemical trials have been initiated to evaluate HMBA as a cytodifferentiation agent in human neoplasms (65). For most human tumors, assay for cytologic evidence of induced differentiation is difficult at best. Following the effects of a differentiation inducing agent by determining c-myc, or c-myb, mRNA levels may provide useful indicators of biological activity of HMBA and be a basis for evaluating whether continued administration of the agent is of interest in terms of potential clinical efficacy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Changes in gene expression during hexamethylene bisacetamide induced erythroleukemia differentiation. 348 Oct 77

Cultured cells from patients inheriting the rare cancer-prone and radiotherapy-sensitive disorder ataxia-telangiectasia (A-T) exhibit anomalies in cell cycle control and protein kinase C (PKC)-mediated upregulation of p53 protein following exposure to ionizing radiation. It remains unclear, however, as to whether this irregularity in a p53-dependent signal transduction pathway controlling the G1/S checkpoint is causally linked to the most consistent molecular hallmark of A-T-namely, marked attenuation in the inhibition of replicative DNA synthesis at early times (< or = 2 h) after irradiation [radioresistant DNA synthesis (RDS)]. We report here that treatment of normal human fibroblast strains with inhibitors of calmodulin (CaM) (i.e. W7 and W13) and CaM-dependent protein kinases II and IV (i.e. KN62) prior to radiation exposure elicits an 'A-T-like' RDS phenotype, whereas treatment with PKC inhibitors (e.g. staurosporine) does not produce this response. Moreover, at 1 h post-gamma irradiation A-T fibroblasts undergo normal induction of p53 protein while exhibiting the RDS trait. At later times (e.g. 4 h) following irradiation, however, these A-T cells contain abnormally low levels of p53 protein, as do their lymphoblastoid cell line counterparts during the entire post-gamma ray incubation period. On the other hand, human cells which either lack the p53 gene completely (i.e. HL60 leukemia cells) or harbor a germline mutation in the gene (i.e. Li-Fraumeni syndrome cells) shut down their DNA replication machinery normally upon sustaining radiation damage. We thus conclude that the transitory delay in DNA synthesis routinely experienced by human cells in the face of radiation injury is mediated through a CaM-dependent regulatory cascade which involves neither PKC nor p53 protein. Accordingly, A-T cells appear to be malfunctional in at least two distinct radiation-responsive signalling pathways, one regulating the G1/S checkpoint and governed by p53 and PKC and another controlling passage through S phase and requiring CaM.
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PMID:Characterization of the signal transduction pathway mediating gamma ray-induced inhibition of DNA synthesis in human cells: indirect evidence for involvement of calmodulin but not protein kinase C nor p53. 747 84


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