Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo.
We show here that a zinc finger transcriptional repressor, Slug, which is aberrantly upregulated by the E2A-HLF oncoprotein in pro-B cell acute leukemia, functions as an antiapoptotic factor in normal hematopoietic progenitor cells. Slug(-/-) mice were much more radiosensitive than wild-type mice, dying earlier and showing accentuated decreases in peripheral blood cell counts, as well as abundant microhemorrhages and widely disseminated bacterial microabscesses throughout the body. Slug expression was detected in diverse subsets of hematopoietic progenitors, but not in more differentiated B and T lymphoid cells, and there was a significant increase in apoptotic (TUNEL-positive) bone marrow progenitor cells in irradiated Slug(-/-) mice compared to wild-type controls. These results implicate Slug in a novel survival pathway that protects hematopoietic progenitors from apoptosis after DNA damage.
Inoue
Akira
A
Department of Experimental Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Seidel
Markus G
MG
Wu
Wenshu
W
Kamizono
Shintaro
S
Ferrando
Adolfo A
AA
Bronson
Roderick T
RT
Iwasaki
Hiromi
H
Akashi
Koichi
K
Morimoto
Akira
A
Hitzler
Johann K
JK
Pestina
Tamara I
TI
Jackson
Carl W
CW
Tanaka
Ryuhei
R
Chong
Miriam J
MJ
McKinnon
Peter J
PJ
Inukai
Takeshi
T
Grosveld
Gerard C
GC
Look
A Thomas
AT
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D050976:Basic-Leucine Zipper Transcription Factors; D001772:Blood Cell Count; D001792:Blood Platelets / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D019610:Cytoprotection; D004249:DNA Damage; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000502:physiology / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000528:radiation effects; D006454:Hemoglobins / Q000378:metabolism; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic; D000071250:Snail Family Transcription Factors; D013154:Spleen / Q000378:metabolism; D015996:Survival Rate; D013950:Thymus Gland / Q000528:radiation effects; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014916:Whole-Body Irradiation; D016335:Zinc Fingers / Q000502:physiology*
D050976:Basic-Leucine Zipper Transcription Factors; D017931:DNA Primers; D004268:DNA-Binding Proteins; C489626:E2a-Hlf fusion protein, mouse; D006454:Hemoglobins; D015514:Oncogene Proteins, Fusion; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53