p73 is a novel member of the p53 family of tumor suppressor proteins which is involved in cellular dierentiation, tumor suppression, and the response to genotoxic stress. The molecular mechanisms regulating p73 activity are still poorly understood. Recently, p73 was found to be a target of the enzymatic activity of c-Abl, a non-receptor tyrosine kinase that potently activated in response to DNA damage. Here, we present evidence that c-Abl induces the phosphorylation of p73 in threonine residues adjacent to prolines, and that the p38 MAP kinase pathway mediates this response. Furthermore, we found that activation of p38 is sucient to enhance the stability of p73, and that the transcriptional activation of p73 by c-Abl requires the activity of p38. These ®ndings indicate that members of the MAP kinases superfamily of signaling molecules can regulate p73, and support a role for the p38 MAP kinase in a novel biochemical pathway by which c-Abl regulates this p53-related molecule. Oncogene (2002) 21, 974 ± 979.
Cancer gene therapy based on the use of suicide genes, such as the thymidine kinase gene, is not producing satisfactory results. Several approaches have been delineated to enhance the therapeutic responses, including augmentation of the bystander effect, the combination of the herpes simplex virus thymidine kinase -ganciclovir ( HSVTK -GCV ) system into replication competent adenoviruses and others. Moreover, because usually less than 20% of human malignant cells are in S -phase, the HSVTK -GCV system is not as efficient as expected. To increase the cytotoxic effects of the HSVTK -GCV system, we hypothesized that concomitant expression of E1a protein, which drives cells to proliferation and S -phase, could increase the effects of the HSVTK -GCV system. Several retroviruses were constructed carrying bicistronic sequences of TK and E1a 12S genes under the control of the CMV promoter. The constructions were tested in murine ( NIH -3T3, MSC11A5 ) and human cells ( IMR90, HeLa, MDA -MB435 ). A clear increase of the HSVTK -GCV system killing effect in nonconfluent cells was observed in the cells studied, especially in NIH -3T3, MSC11A5, IMR90, and MDA -MB435 expressing cells. In confluence, the NIH3T3 and IMR90 E1a -TK -expressing cells were also very sensitive and most malignant E1a -TK -expressing cells showed an irreversible G2 -M cell cycle arrest. Moreover, the concomitant expression of adenovirus E1a and the HSVTK -GCV system increased the sensitivity to anticancer agents such as cisplatin. These results show that adenovirus E1a protein expression clearly enhances the cytotoxic effects of the HSVTK -GCV system and the response to treatment with cisplatin.
Since the discovery of the myc gene, few genes are likely to have such influence on biomedical research. The diversity of the biological functions regulated by this transcription factor and its impact in human health have attracted investigators from many different fields. The development of conditional knockout mouse models has allowed for the characterization of Myc-driven molecular mechanisms in primary cells in physiological and pathological conditions. In this review, we discuss some of the main functions and recent findings regarding c-Myc in in vivo B lymphocyte differentiation from early progenitors to terminally differentiated cells.
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