Blood, 1 February 2002, Vol. 99, No. 3, pp. 729-729
ATF4: a novel regulator of cell growth
Activating transcription factor-4 (ATF4) is a member of the
ATF/CREB subfamily of basic region-leucine zipper proteins. ATF4 forms
homodimers or heterodimers by interacting with itself or other proteins
through its leucine zipper motif. Potential partners of ATF4 include
members of the AP-1 and C/EBP families, c-maf, and Nfe2-related factors
Nrf1 and Nrf2. Previous studies have shown that ATF4 is required for
lens formation in mice. Masuoka and Townes (page 736) now report that
ATF4 has a role in definitive hematopoietic development. ATF4-deficient
embryos are severely anemic. The fetal livers from these embryos
contain fewer hematopoietic progenitors, and the colonies contain fewer
cells, than controls. Whereas the lens defect is due, at least in part,
to p53-dependent apoptosis, no increase in apoptosis was noted in
ATF4-deficient fetal livers. Thus, the fetal anemia appears to be due
to a defect in erythroid proliferation. Furthermore, ATF4-deficient
mice are approximately half the size of littermate controls and have
delayed hair growth. Fibroblasts from ATF4-deficient embryos have a
prolonged doubling time. These results suggest that ATF4 deficiency
impairs cell growth in a variety of tissues.
ATF4 joins a growing list of genes, whose
disruption causes transient fetal anemia. These genes, which include
"flexed", E2f4, and Stat5a/Stat5b,
are not essential for erythropoiesis. Rather, they appear to be on
ancillary pathways that support erythropoiesis at specific stages of
development or under conditions of stress. Additional studies are
needed to determine the exact role of ATF4 in hematopoietic regulation.
It is interesting that some of the potential dimerization partners of
ATF4 may also have a role in fetal hematopoiesis. Nrf1 deficiency is
associated with fetal anemia, while c-maf deficiency is associated with
fetal anemia and a defect in lens development. The similarity of these
phenotypes to the ATF4 phenotype raises the possibility of a
functionally relevant interaction between ATF4 and Nrf1 or
c-maf.
Paul A. Ney
St Jude Children's Research Hospital
