GAAP‐1: a transcriptional activator of p53 and IRF‐1 possesses pro‐apoptotic activity

The mechanisms that regulate the transcription of the tumour suppressor genes p53 and IRF‐1 are poorly understood. We have characterized a 68‐kDa transcription factor, GAAP‐1 (gatekeeper of apoptosis activating proteins), encoded by an alternative splice product of the PRDII‐BF1 gene, that recognizes a novel regulatory element within the p53 and IRF‐1 promoters. Transfection of U937 cells with GAAP‐1 activates p53 and IRF‐1 expression and leads to apoptosis, whereas over‐expression of GAAP‐1 in K562 cells that lack p53 and IRF‐1 induces cell differentiation. Alterations in the 6p24 locus containing the GAAP‐1 gene are frequent in acute myelogenous leukemia (AML), and AML‐derived cell lines display reduced GAAP‐1 mRNA levels. Together, these results suggest that GAAP‐1 acts as a gatekeeper at a critical point in the tumour suppressor gene pathway.

[1]  S. Sukumar,et al.  Compromised HOXA5 function can limit p53 expression in human breast tumours , 2000, Nature.

[2]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[3]  A. Deisseroth,et al.  A novel interferon-inducible domain: structural and functional analysis of the human interferon regulatory factor 1 gene promoter , 1993, Molecular and cellular biology.

[4]  I. Wang,et al.  Regulation of Apoptosis in Myeloid Cells by Interferon Consensus Sequence–Binding Protein , 1999, The Journal of experimental medicine.

[5]  T. Taniguchi,et al.  IRF family of transcription factors as regulators of host defense. , 2001, Annual review of immunology.

[6]  K. Bhalla,et al.  Enforced expression of Bcl-XS induces differentiation and sensitizes chronic myelogenous leukemia-blast crisis K562 cells to 1-beta-D-arabinofuranosylcytosine-mediated differentiation and apoptosis. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[7]  C. Lallemand,et al.  Identification of a Novel Transcriptional Regulatory Element Common to the p53 and Interferon Regulatory Factor 1 Genes* , 1997, The Journal of Biological Chemistry.

[8]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[9]  T. Naoe,et al.  Prognostic value of p53 gene mutations and the product expression in de novo acute myeloid leukemia , 2000, European journal of haematology.

[10]  H. Wu,et al.  NF-kappa B activation of p53. A potential mechanism for suppressing cell growth in response to stress. , 1994, The Journal of biological chemistry.

[11]  P A Pevzner,et al.  Gene hunting without sequencing genomic clones: finding exon boundaries in cDNAs. , 1998, Genomics.

[12]  M. Lübbert,et al.  p53 in chronic myelogenous leukemia. Study of mechanisms of differential expression , 1988, The Journal of experimental medicine.

[13]  P. Sharp,et al.  A large protein containing zinc finger domains binds to related sequence elements in the enhancers of the class I major histocompatibility complex and kappa immunoglobulin genes , 1990, Molecular and cellular biology.

[14]  R. Gaynor,et al.  Transcription factor PRDII-BF1 activates human immunodeficiency virus type 1 gene expression , 1994, Journal of virology.

[15]  T. Maniatis,et al.  A DNA-binding protein containing two widely separated zinc finger motifs that recognize the same DNA sequence. , 1990, Genes & development.

[16]  T. Soussi.  The p53 Tumor Suppressor Gene: From Molecular Biology to Clinical Investigation , 2000, Annals of the New York Academy of Sciences.

[17]  R. Gaynor,et al.  Regulation of human immunodeficiency virus enhancer function by PRDII-BF1 and c-rel gene products , 1992, Journal of virology.

[18]  Thomas J. White,et al.  PCR protocols: a guide to methods and applications. , 1990 .

[19]  A. Brothman,et al.  Nonrandom rearrangements of 6p in malignant hematological disorders. , 2000, Cancer genetics and cytogenetics.