): Leukemia, as with cancer in general, is characterized by a loss of normal cellular control over growth and differentiation. The E2A gene, which is strongly associated with human leukemias, encodes three basic-helix-loop-helix transcription factors (E12, E47, E2-5) which have an established role in the regulation of growth and differentiation in mammalian cells. E2A is highly expressed in the absence of growth factors and overexpression of E2A can arrest cells in G1. The preliminary data of the applicants indicate that one transcriptional target of E2A regulation which may mediate some of its growth suppressive properties is the cyclin-dependent kinase inhibitor, p2l(WAFl/CIP1). E2A's activation of p2l appears to be p53-independent and is inhibited in transformed cells and in the presence of the oncoproteins, TAL1 and Ras. Recent evidence suggests that a n o t h er cyclin-dependent kinase inhibitor, pl6(INK4a), may also be transcriptionally regulated by E2A. To clarify E2A's role in growth regulation, the following specific aims are proposed: 1. Evaluate the role of E2A in p21 (WAF1/CIP1) expression. 2. Assess the influence of TAL1, Id3, Ras and Myc on the E2A-p2l pathway. 3. Identify other growth suppressive genes regulated by E2A. Fulfillment of these specific aims will contribute to the understanding of E2A's normal role in the regulation of cellular growth and provide new insight into its contribution to the development of leukemia.
|Ogawa, Ryosuke; Streiff, Michael B; Bugayenko, Artem et al. (2002) Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. Blood 99:3390-7|