bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis.

Inactivation of p53-dependent apoptosis promotes oncogenic transformation, tumor development, and resistance to many cytotoxic anticancer agents. p53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis. To determine whether bax is required for p53-dependent apoptosis, the effects of bax deficiency were examined in primary fibroblasts expressing the E1A oncogene, a setting where apoptosis is dependent on endogenous p53. We demonstrate that bax can function as an effector of p53 in chemotherapy-induced apoptosis and contributes to a p53 pathway to suppress oncogenic transformation. Furthermore, we show that additional p53 effectors participate in these processes. These p53-controlled factors act synergistically with Bax to promote a full apoptotic response, and their action is suppressed by the Bcl-2 and E1B 19K oncoproteins. These studies demonstrate that Bax is a determinant of p53-dependent chemosensitivity and illustrate how p53 can promote apoptosis by coordinating the activities of multiple effectors.

[1]  John Calvin Reed,et al.  Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. , 1994, Oncogene.

[2]  E. Newcomb,et al.  p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression , 1993 .

[3]  H C Hemker,et al.  Binding of vascular anticoagulant alpha (VAC alpha) to planar phospholipid bilayers. , 1990, The Journal of biological chemistry.

[4]  S. Lowe,et al.  Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. , 1993, Genes & development.

[5]  James Brugarolas,et al.  Radiation-induced cell cycle arrest compromised by p21 deficiency , 1995, Nature.

[6]  C. Prives,et al.  p53: puzzle and paradigm. , 1996, Genes & development.

[7]  T. Aas,et al.  Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients , 1996, Nature Medicine.

[8]  K. Franssila,et al.  Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. , 1995, Cancer research.

[9]  L. Holmberg,et al.  Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy , 1995, Nature Medicine.

[10]  R. Weinberg,et al.  Tumor spectrum analysis in p53-mutant mice , 1994, Current Biology.

[11]  D. Housman,et al.  Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Housman,et al.  p53 status and the efficacy of cancer therapy in vivo. , 1994, Science.

[13]  S. Lowe,et al.  Cancer therapy and p53. , 1995, Current opinion in oncology.

[14]  John Calvin Reed,et al.  Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. , 1994, Oncogene.

[15]  Stephen J. Elledge,et al.  Mice Lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control , 1995, Cell.

[16]  E. White,et al.  Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. , 1993, Genes & development.

[17]  B. Quesnel,et al.  p53 Mutations Are Associated With Resistance to Chemotherapy and Short Survival in Hematologic Malignancies , 1994 .

[18]  S. Korsmeyer,et al.  Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death , 1993, Cell.

[19]  John Calvin Reed,et al.  Tumor suppressor p53 is a direct transcriptional activator of the human bax gene , 1995, Cell.

[20]  S. Ménard,et al.  A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. , 1996, Cancer research.

[21]  E. White,et al.  Bcl-2 blocks p53-dependent apoptosis , 1994, Molecular and cellular biology.

[22]  J. Roth,et al.  Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. , 1994, Cancer research.

[23]  K. Kohn,et al.  p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. , 1994, Cancer research.

[24]  E. White,et al.  The E1B 19K protein blocks apoptosis by interacting with and inhibiting the p53-inducible and death-promoting Bax protein. , 1996, Genes & development.

[25]  S. Korsmeyer,et al.  Bax-Deficient Mice with Lymphoid Hyperplasia and Male Germ Cell Death , 1995, Science.