PubMed · 13507071
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E B EVANS, M H SCHREIBER. 1957. Osteogenic sarcoma.. https://pubmed.ncbi.nlm.nih.gov/13507071/
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The p53 tumor suppressor is phosphorylated in response to various cellular stress signals, such as DNA damage, leading to its release from MDM2 and consequent stabilization and activation as a transcription factor. In human U2OS cells, treatment with adriamycin causes p53 to be phosphorylated on all six serine residues tested, leading to the dissociation of p53 from MDM2 and transcription of the p21 and mdm2 genes. In contrast, in these cells, IPTG-dependent induction of p14ARF, which sequesters MDM2 away from p53, does not lead to detectable phosphorylation of any of the five N-terminal serine residues tested (6, 9, 15, 20, 37). Only C-terminal serine 392 is phosphorylated. However, the increase of p21 and mdm2 mRNAs was indistinguishable following treatment with adriamycin or induction of p14ARF. By using cDNA arrays to examine global p53-dependent gene expression in response to adriamycin or p14ARF, we found that most genes were regulated similarly by the two treatments. However, a subset of p53-regulated genes whose products have proliferative roles or regulate VEGF activity, newly described here, are repressed by p14ARF much more than by adriamycin. We conclude that the phosphorylation of p53 on N-terminal serine residues is not required for increased transcription of the great majority of p53-responsive genes and that the induction of p53 by p14ARF, with little phosphorylation, leads to substantial repression of genes whose products have roles in proliferation.
BACKGROUND: Susceptibility to extracellular matrix and growth factors has been demonstrated to play a critical role in the development of prostate cancer (PCa) metastases. The aim of this study was to elucidate some mechanisms by which stroma controls tumor progression. METHODS: In our study we tested the growth ability of the LNCaP human prostatic cell line in steroid-free culture conditions in response to osteopontin (OPN), a non-collageneous matrix protein, localized in large amounts in the bone. RESULTS: In the LNCaP cell model, OPN stimulates cell proliferation in serum-free medium and colony growth at high dilution but this effect is visible only in presence of epidermal growth factor (EGF). Proliferation induced by OPN is accompanied by a sustained activation of EGF receptor (EGFR) whose phosphorylation is detectable up to 12 hr after treatment in association with EGF. The colocalization of integrin beta1, a ligand of OPN, and of EGFR on the cellular membrane, suggests that the association of these cell surface receptors may be the principal mechanism involved in the long-term activation of the EGFR. CONCLUSIONS: Our data describe a new possible mechanism involved in the establishment of bone metastases which may also account for the formation of androgen-independent cellular clones, frequently responsible of the clinical progression of PCa.
The signals generated by the IFNgamma receptor to initiate mRNA translation and generation of protein products that mediate IFNgamma responses are largely unknown. In the present study, we provide evidence for the existence of an IFNgamma-dependent signaling cascade activated downstream of the phosphatidylinositol (PI) 3'-kinase, involving the mammalian target of rapamycin (mTOR) and the p70 S6 kinase. Our data demonstrate that p70 S6K is rapidly phosphorylated and activated during engagement of the IFNgamma receptor in sensitive cell lines. Such activation of p70 S6 kinase is blocked by pharmacological inhibitors of the PI 3' kinase and mTOR, and is abrogated in double-knockout mouse embryonic fibroblasts for the alpha and beta isoforms of the p85 regulatory subunit of the PI 3'-kinase. The IFNgamma-activated p70 S6 kinase subsequently phosphorylates the 40S S6 ribosomal protein on serines 235/236, to regulate IFNgamma-dependent mRNA translation. In addition to phosphorylation of 40S ribosomal protein, IFNgamma also induces phosphorylation of the 4E-BP1 repressor of mRNA translation on threonines 37/46, threonine 70, and serine 65, sites whose phosphorylation is required for the inactivation of 4E-BP1 and its dissociation from the eukaryotic initiation factor-4E (eIF4E) complex. Thus, engagement of the PI 3'-kinase and mTOR by the IFNgamma receptor results in the generation of two distinct signals that play roles in the initiation of mRNA translation, suggesting an important role for this pathway in IFNgamma signaling.