Fusion with E2A Converts the Pbx1 Homeodomain Protein into a Constitutive Transcriptional Activator in Human Leukemias Carrying the t(1;19) Translocation

Lü, Qiang; Wright, Darin L.; Kamps, Mark P.

doi:10.1128/mcb.14.6.3938-3948.1994

Cited by 4 publications

(1 citation statement)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FGF15 was originally discovered by the representational difference analysis in a murine fibroblast cell line NIH3T3 transfected with either an empty vector or vector containing cDNA of E2A-Pbx1b, a fusion protein with pre-B cell leukemia containing the t(1;19) chromosome translocation [ 117 , 118 ]. The most striking feature in the structure of FGF15 was that the predicted amino acid sequence has a putative signal peptide, which does not exist in the canonical FGF family members [ 119 ].…”

Section: Regulation Production and Biological Function Of Fgf15/19mentioning

confidence: 99%

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Katafuchi,

Makishima

2022

IJMS

View full text Add to dashboard Cite

Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

show abstract

Section: Regulation Production and Biological Function Of Fgf15/19mentioning

confidence: 99%

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Katafuchi,

Makishima

2022

IJMS

View full text Add to dashboard Cite

show abstract

Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia

McWhirter

Neuteboom

Wancewicz

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

134

107

View full text Add to dashboard Cite

Critical Role for a Single Leucine Residue in Leukemia Induction by E2A-PBX1

Bayly

Murase

Hyndman

et al. 2006

Molecular and Cellular Biology

View full text Add to dashboard Cite

In roughly 5% of cases of acute lymphoblastic leukemia, a chromosomal translocation leads to expression of the oncogenic protein E2A-PBX1. The N-terminal portion of E2A-PBX1, encoded by the E2A gene, is identical in sequence to the corresponding portion of the E proteins E12/E47 and includes transcriptional activation domains. The C terminus consists of most of the HOX interacting transcription factor PBX1, including its DNA-binding homeodomain. Structure-function correlative experiments have suggested that oncogenesis by E2A-PBX1 requires an activation domain, called AD1, at the extreme N terminus. We recently demonstrated that a potentially helical portion of AD1 interacts directly with the transcriptional coactivator protein cyclic AMP response element-binding protein (CBP) and that this interaction is essential in the immortalization of primary bone marrow cells in tissue culture. Here we show that a conserved LXXLL motif within AD1 is required in the interaction between E2A-PBX1 and the KIX domain of CBP. We show by circular dichroism spectroscopy that the LXXLL-containing portion of AD1 undergoes a helical transition upon interacting with the KIX domain and that amino acid substitutions that prevent helix formation prevent both the KIX interaction and cell immortalization by E2A-PBX1. Perhaps most strikingly, substitution of a single, conserved leucine residue (L20) within the LXXLL motif impairs leukemia induction in mice after transplantation with E2A-PBX1-expressing bone marrow. The KIX domain of CBP mediates well-characterized interactions with several transcription factors of relevance to leukemia induction. Circumstantial evidence suggests that the side chain of L20 might interact with a deep hydrophobic pocket in the KIX domain. Therefore, our results serve to identify a potential new drug target.The neoplastic cells in acute lymphoblastic leukemia (ALL) frequently contain recurrent somatic chromosomal abnormalities that contribute to their abnormal accumulation and function. A reciprocal translocation between chromosome bands 1q23 and 19p13.3 is detectable by conventional cytogenetic techniques in roughly 5% of cases of ALL (10). Of that 5% of cases, in 90 to 95% the presence of t(1;19) leads to the fusion of portions of the E2A gene on chromosome 19 with portions of the PBX1 gene on chromosome 1 and to expression of chimeric transcription factors called E2A-PBX1a and E2A-PBX1b (these isoforms are generated by alternative splicing of the PBX1 portion of the premRNA) (20,30). Beyond the consistent association with leukemia, the idea of the oncogenic potential of E2A-PBX1 is supported by abundant experimental evidence (reviewed in reference 24). Therefore, it seems likely that elucidating the molecular mechanisms by which E2A-PBX1 contributes to abnormal cellular behavior may uncover novel avenues in the development of better therapies for cases of ALL.E2A-PBX1 incorporates a PBX1-derived homeodomain near its C terminus and, like wild-type PBX1 proteins, can bind to PBX1 recognition sequences in coop...

show abstract

Fusion with E2A Converts the Pbx1 Homeodomain Protein into a Constitutive Transcriptional Activator in Human Leukemias Carrying the t(1;19) Translocation

Cited by 4 publications

References 40 publications

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia

Critical Role for a Single Leucine Residue in Leukemia Induction by E2A-PBX1

Contact Info

Product

Resources

About