Cell Growth & Differentiation, Vol 9, Issue 1 59-69, Copyright © 1998 by American Association of Cancer Research

ARTICLES

E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation

DK Strom, JL Cleveland, S Chellappan, J Nip and SW Hiebert
Department of Biochemistry and the Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

Interleukin 3 (IL-3)-dependent 32D.3 myeloid cells are an attractive model system for the analysis of hematopoietic cell growth, differentiation, and apoptosis. In these cells, E2F-3, E2F-4, and DP-1 are regulated by both IL-3 and granulocyte colony-stimulating factor (G-CSF), whereas E2F-1 was expressed at low levels and was not regulated by either cytokine. E2F-2 and E2F-5 were not detectable. To examine phenotypes associated with the loss of normal cell cycle regulation by pRb, we established E2F-1- and E2F-3-overexpressing cell lines. In contrast to E2F-1, E2F-3 overexpression did not accelerate apoptosis or promote S-phase entry in the absence of IL-3, demonstrating that they are not functionally redundant. In addition, when cells were cultured in G-CSF to stimulate granulocytic differentiation, E2F-1 overexpression overrode survival functions provided by G-CSF and serum and induced apoptosis. In contrast, cells overexpressing E2F-3 exhibited normal granulocytic differentiation. Bcl-2 coexpression blocked E2F-1-induced apoptosis in the presence of G-CSF. However, these cells were blocked in the granulocytic differentiation program at the metamyelocyte stage and remained dependent on G-CSF for continuous culture. Cells overexpressing both E2F-1 and Bcl-2 exhibited slowed but continuous cell cycling in the absence of IL-3 until they eventually succumbed to apoptosis. Therefore, E2F-1, but not E2F-3, can temporally replace the requirement for growth factors to promote cell cycle progression, and in terminally differentiating cells, this leads to a block in differentiation and induction of apoptosis.

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