PubMed · 6994622
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N Colman, V Herbert. 1980. Folate-binding proteins.. https://doi.org/10.1146/annurev.me.31.020180.002245
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We have recently shown that human papillomavirus (HPV16) E6 oncoprotein exhibits two separate biological activities in genital keratinocytes (PHKs). E6 protein by itself is capable of inducing colonies of proliferating cells resistant to serum and calcium-induced differentiation, whereas both E6 and E7 are required for immortalization of PHK. Using epitope-tagged E6 carboxy-terminal truncation mutants, we mapped the domain between amino acid residues 132 and 141 as being essential for the induction of differentiation resistance (L. Sherman and R. Schlegel, J. Virol. 70, 3269-3279, 1996). To determine whether E6 protein's ability to alter PHK response to serum and calcium was associated with its ability to inactivate p53, we evaluated each of the above E6 mutants and three E6 natural variants in these respective assays. Our results demonstrate that the E6 region spanning residues 132-141 is required for p53 degradation and for abrogation of p53 transactivation, suggesting a possible correlation between E6 biological activity in altering differentiation and loss of p53 function. To evaluate whether selective inactivation of p53 is sufficient for altering the response of PHK to serum and calcium we investigated the capacity of plasmids encoding a dominant mutant human p53 and human MDM-2 to functionally substitute for E6 in colony formation in PHK. Plasmids were verified for their ability to inactivate wild-type p53 by testing their capacity to abrogate the p53 transactivation function. The results obtained showed that vectors encoding human MDM-2 and mutant p53, while active in inhibition of p53-dependent transactivation and capable of expressing stable proteins in PHK, failed to induce colonies of proliferating cells resistant to serum and calcium differentiation. These data argue that p53 inactivation may not be the sole E6 function required for altering the response of PHK to serum- and calcium-triggered differentiation.
We have demonstrated that monocyte-derived macrophages (Mphi) from HIV+ individuals are deficient in their capacity to phagocytose Histoplasma capsulatum (Hc) yeasts, and are more permissive for the intracellular growth of Hc. To determine whether these defects in Mphi function were caused by HIV infection of the Mphi and/or by pathological events associated with HIV infection, cultured normal human Mphi were infected with the HIV-1BaL strain. Virus production, quantified by reverse transcriptase activity and p24 antigen, was evident on day 8 after infection and peaked on day 16. On days 12, 16, and 20 after infection, HIV-1-infected Mphi were deficient in their capacity to recognize and bind Hc yeasts compared with control Mphi, and also were more permissive for the intracellular growth of Hc. Culture of normal Mphi with the envelope glycoprotein gp120 inhibited phagocytosis of Hc yeasts by Mphi in a concentration-dependent manner, but did not cause more rapid intracellular growth of Hc. Normal Mphi cultured in the serum of HIV+ individuals with impaired Mphi function subsequently were deficient in their capacity to phagocytose Hc yeasts, and were more permissive for the intracellular growth of yeasts compared with Mphi cultured in normal serum. Conversely, culture of normal Mphi in the serum of HIV+ patients with normal Mphi function did not affect the interaction of Hc yeasts with Mphi. Moreover, when Mphi from HIV+ individuals that were initially defective in host defense against Hc were cultured in normal HIV- serum, normal Mphi function was demonstrated. Adsorption of gp120 from the serum of two HIV+ patients removed the capacity of the serum to cause a Mphi defect in phagocytosis of Hc, but had no effect on the capacity of the serum to cause accelerated intracellular growth. These data demonstrate that observed defects in Mphi interaction with Hc yeasts may be caused by gp120 and other, as yet unknown serum component(s) probably released into serum by HIV-infected cells.
The proliferation response of human peripheral blood mononuclear cells (PBMC) to concanavalin A (con A) was tested in a medium with or without addition of fetal calf serum (FCS) or a serum substitute. The time profile of the proliferative response of PBMC to con A was different in cells cultured in a medium supplemented with or without FCS. This different pattern occurred for the con A-induced DNA-synthesis as well as for the RNA- or protein-synthesis. The peak proliferation rate and the stimulation index of proliferation of human PBMC to con A was also higher when the cells were cultured in a medium with 10% FCS compared to cells cultured in a FCS-free medium. Substitution of the fetal calf serum by a serum substitute even induced a profound inhibition of the de novo synthesis of DNA in human PBMC. The results indicate that a lymphocyte proliferation response to con A can still be obtained in a culture medium where no FCS was added, although a weaker stimulation occurred in comparison to a culture medium with FCS. However, addition of a serum substitute caused a marked inhibition of the lymphocyte proliferation rate.