Abstract
SCL/Tal-1 is a helix-loop-helix (HLH) transcription factor required for blood cell development, whose abnormal expression is responsible for induction of T-cell acute lymphoblastic leukemia. We show here that SCL/Tal-1 is a key target of caspases in developing erythroblasts. SCL/Tal-1 degradation occurred rapidly after caspase activation and preceded the cleavage of the major erythroid transcription factor GATA-1. Expression of a caspase-resistant SCL/Tal-1 in erythroid progenitors was able to prevent amplification of caspase activation, GATA-1 degradation and impaired erythropoiesis induced by growth factor deprivation or death receptor triggering. The potent proerythropoietic activity of uncleavable SCL/Tal-1 was clearly evident in the absence of erythropoietin, a condition that did not allow survival of normal erythroid cells or expansion of erythroblasts expressing caspase-resistant GATA-1. In the absence of erythropoietin, cells expressing caspase-resistant SCL/Tal-1 maintain high levels of Bcl-X(L), which inhibits amplification of the caspase cascade and mediates protection from apoptosis. Thus, SCL/TAL-1 is a survival factor for erythroid cells, whereas caspase-mediated cleavage of SCL/Tal-1 results in amplification of caspase activation, GATA-1 degradation and impaired erythropoiesis.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Chloromethyl Ketones / pharmacology
-
Antibodies / pharmacology
-
Apoptosis / drug effects
-
B-Lymphocytes / cytology
-
B-Lymphocytes / drug effects
-
B-Lymphocytes / metabolism
-
Basic Helix-Loop-Helix Transcription Factors
-
Blotting, Western
-
Caspase 3
-
Caspase 7
-
Caspase 8
-
Caspases / metabolism*
-
Cell Division / drug effects
-
Cloning, Molecular
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism*
-
Down-Regulation
-
Enzyme Precursors / metabolism
-
Erythroblasts / cytology
-
Erythroblasts / drug effects
-
Erythroblasts / metabolism
-
Erythroid-Specific DNA-Binding Factors
-
Erythropoiesis / physiology*
-
Erythropoietin / deficiency
-
Erythropoietin / pharmacology
-
GATA1 Transcription Factor
-
GATA2 Transcription Factor
-
Gene Expression Regulation
-
Green Fluorescent Proteins
-
Helix-Loop-Helix Motifs / genetics
-
Helix-Loop-Helix Motifs / physiology
-
Humans
-
Luminescent Proteins / genetics
-
Luminescent Proteins / metabolism
-
Microscopy, Fluorescence
-
Mutagenesis, Site-Directed
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / metabolism
-
T-Cell Acute Lymphocytic Leukemia Protein 1
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
bcl-X Protein
-
fas Receptor / immunology
-
fas Receptor / physiology
Substances
-
Amino Acid Chloromethyl Ketones
-
Antibodies
-
BCL2L1 protein, human
-
Basic Helix-Loop-Helix Transcription Factors
-
DNA-Binding Proteins
-
Enzyme Precursors
-
Erythroid-Specific DNA-Binding Factors
-
GATA1 Transcription Factor
-
GATA1 protein, human
-
GATA2 Transcription Factor
-
GATA2 protein, human
-
Luminescent Proteins
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-bcl-2
-
Recombinant Fusion Proteins
-
T-Cell Acute Lymphocytic Leukemia Protein 1
-
Transcription Factors
-
bcl-X Protein
-
benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
-
fas Receptor
-
Erythropoietin
-
TAL1 protein, human
-
Green Fluorescent Proteins
-
CASP3 protein, human
-
CASP7 protein, human
-
CASP8 protein, human
-
Caspase 3
-
Caspase 7
-
Caspase 8
-
Caspases