Biomedical subjects

Lynne Hananeia

Publications and source records attributed to Lynne Hananeia.

3 recordsLinked to original sources

PubMed2005

Y-box factor YB1 controls p53 apoptotic function.

Nuclear localization and high levels of the Y-box-binding protein YB1 appear to be important indicators of drug resistance and tumor prognosis. YB1 also interacts with the p53 tumor suppressor protein. In this paper, we have continued to explore YB1/p53 interactions. We report that transcriptionally active p53 is required for nuclear localization of YB1. We go on to show that nuclear YB1 regulates p53 function. Our data demonstrate that YB1 inhibits the ability of p53 to cause cell death and to transactivate cell death genes, but does not interfere with the ability of p53 to transactivate the CDKN1A gene, encoding the kinase p21(WAF1/CIP1) required for cell cycle arrest, nor the MDM2 gene. We also show that nuclear YB1 is associated with a failure to increase the level of the Bax protein in normal mammary epithelial cells after stress activation of p53. Together these data suggest that (nuclear) YB1 selectively alters p53 activity, which may in part provide an explanation for the correlation of nuclear YB1 with drug resistance and poor tumor prognosis.

Active Transport, Cell Nucleus↗

PubMed2003

The proline-rich region of mouse p53 influences transactivation and apoptosis but is largely dispensable for these functions.

The N-terminal proline-rich domain of human p53 has been shown to be important for the induction of apoptosis. However, the corresponding region in mouse and other species is not highly conserved and has been less well studied. In this paper, we have characterized mutants with deletions in this region of mouse p53. Our results demonstrate that deletions in the proline-rich domain have varying effects on function ranging from no effect to severe impairment of cell death activity, depending on precisely which residues are deleted. We also show that the mutants differ in their ability to transactivate different p53 target promoters. Although we have been able to obtain mutants selectively impaired for apoptosis, our data are not generally consistent with this region being a functional domain. The data are more consistent with the interpretation that the region influences function by altering local protein structure which may affect promoter discrimination.

Amino Acid Sequence↗

PubMed2003

Nuclear localization of Y-box factor YB1 requires wild-type p53.

Nuclear localization and high levels of the Y-box binding protein YB1 appear to be important indicators of drug resistance and tumor prognosis. YB1 also interacts with the p53 tumor suppressor protein. In this paper, we explore a role for p53 in the nuclear localization of YB1. We report that various genotoxic stresses induce nuclear localization of YB1 in a small proportion of treated cells, but only in cells with wild-type p53. We go on to show directly that functional p53 is required for YB1 to translocate to the nucleus. Tumor-associated p53 mutants however are attenuated for YB1 nuclear localization as are mutants mutated in the proline-rich domain of p53. These data link the DNA-damage response of p53 to YB1 nuclear translocation. In addition, we find that YB1 inhibits p53-induced cell death and its ability to trans-activate promoters of genes involved in cell death signaling. Together these data suggest that some forms of p53 cause YB1 to accumulate in the nucleus, which in turn inhibits p53 activity. These results provide a possible explanation for the correlation of nuclear YB1 with drug resistance and poor prognosis in some tumor types, and for the first time implicate p53 in the process of nuclear translocation.

Active Transport, Cell Nucleus↗