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Thrombopoietin upregulates the promoter conformation of p53 in a proliferation-independent manner coincident with a decreased expression of Bax: potential mechanisms for survival enhancing effects.

Abstract：

:Thrombopoietin (Tpo) has proliferative and maturational effects on immature and more committed cells, respectively. We previously reported a role for Tpo as a survival factor in the factor-dependent human cell line M07e by demonstrating that Tpo suppresses apoptosis in the absence of induced proliferation. Wild-type p53 is a tumor suppressor gene that can play a vital role in mediating growth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. Wild-type p53 can switch from a suppressor conformation, with an antiproliferative, pro-apoptotic phenotype, to a promoter conformation that has a diminished ability to mediate cell cycle arrest and apoptosis. In an effort to elucidate the mechanisms through which Tpo suppresses apoptosis, we investigated the effects of Tpo treatment on p53-mediated apoptosis in M07e cells. Tpo upregulated the expression of the promoter conformation of p53 in M07e cells coincident with a downregulation of Bax and Mdm2 protein levels. Protein levels of Bcl-2 and Bcl-xL did not significantly vary as a function of growth-factor stimulation. Conversely, the levels of suppressor conformation p53 were maximal when M07e was in a growth arrested state and decreased during factor stimulation. Furthermore, Tpo treatment induced an extranuclear buildup and greatly weakened the DNA binding capacity of p53. p53-specific antisense oligonucleotide treatment recapitulated the effects of Tpo treatment on the levels of Bax, Mdm-2, and Bcl-2. These results suggest that Tpo is suppressing growth factor withdrawal induced-apoptosis, at least in part, by downregulating the expression of pro-apoptotic Bax protein levels, through modulating the conformation of p53, which results in a functional inactivation of its pro-apoptotic abilities.

journal_name

Blood

journal_title

Blood

authors

Ritchie A,Gotoh A,Gaddy J,Braun SE,Broxmeyer HE

subject

Has Abstract

pub_date

1997-12-01 00:00:00

pages

4394-402

issue

eissn

0006-4971

issn

1528-0020

journal_volume

pub_type

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Thrombopoietin upregulates the promoter conformation of p53 in a proliferation-independent manner coincident with a decreased expression of Bax: potential mechanisms for survival enhancing effects.