Control of erythroid cell production via caspase-mediated cleavage of transcription factor SCL/Tal-1.
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.
Zeuner
A
A
Department of Hematology and Oncology, Istituto Superiore di Sanità, Rome 00161, Italy.
Eramo
A
A
Testa
U
U
Felli
N
N
Pelosi
E
E
Mariani
G
G
Srinivasula
S M
SM
Alnemri
E S
ES
Condorelli
G
G
Peschle
C
C
De Maria
R
R
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004792:Enzyme Precursors / Q000378:metabolism; D004900:Erythroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000172:deficiency / Q000494:pharmacology; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D018257:Helix-Loop-Helix Motifs / Q000235:genetics / Q000502:physiology; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
D000590:Amino Acid Chloromethyl Ketones; D000906:Antibodies; D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D050981:Erythroid-Specific DNA-Binding Factors; D004921:Erythropoietin; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; D051020:bcl-X Protein; D019014:fas Receptor; C494811:BCL2L1 protein, human; C494688:GATA1 protein, human; C494711:GATA2 protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C067143:TAL1 protein, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505530:CASP8 protein, human