The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis.
TACC3 is a centrosomal/mitotic spindle-associated protein that is highly expressed in a cell cycle-dependent manner in hematopoietic lineage cells. During embryonic development, TACC3 is expressed in a variety of tissues in addition to the hematopoietic lineages. TACC3 deficiency causes an embryonic lethality at mid- to late gestation involving several lineages of cells. Hematopoietic stem cells, while capable of terminal differentiation, are unable to be expanded in vitro or in vivo in reconstitution approaches. Although gross alterations in centrosome numbers and chromosomal segregation are not observed, TACC3 deficiency is associated with a high rate of apoptosis and expression of the p53 target gene, p21(Waf1/Cip1). Hematopoietic stem cell functions, as well as deficiencies in other cell lineages, can be rescued by combining the TACC3 deficiency with p53 deficiency. The results support the concept that TACC3 is a critical component of the centrosome/mitotic spindle apparatus and its absence triggers p53-mediated apoptosis.
Piekorz
Roland P
RP
Howard Hughes Medical Institute, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Hoffmeyer
Angelika
A
Duntsch
Christopher D
CD
McKay
Catriona
C
Nakajima
Hideaki
H
Sexl
Veronika
V
Snyder
Linda
L
Rehg
Jerold
J
Ihle
James N
JN
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D015152:Blotting, Northern; D018385:Centrosome / Q000378:metabolism*; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D005804:Genes, Lethal; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D008869:Microtubule-Associated Proteins; C120551:TACC3 protein, human; D016159:Tumor Suppressor Protein p53