Project Details
Description
DESCRIPTION (Adapted from the Investigator's abstract): This renewal application seeks to continue studies on the regulation of B-cell lymphoma growth and apoptosis. The investigator's laboratory has found that anti-Mu, but not anti-delta, treatment of a set of lymphomas in early G1 results in arrest of their growth prior to the G1/S border and then apoptosis. They have found that the initial step is activation of src family protein tyrosine kinases, which promote the docking and phosphorylation of second messenger substrates. During this process synthesis of c-myc transiently appears and disappears. It is now clear that this growth arrest results from action of anti-Mu on components of the kinase:cyclin complexes that regulate phosphorylation of the retinoblastoma gene product, pRb. In the continuing investigation the overall goal will be to connect the initial tyrosine phosphorylation events to altered myc transcription and modification of the cyclin:cdk complexes that act on pRb. This will be done using a series of CD8 chimeric proteins and mutant constructs to identify downstream substrates for phosphorylation by Ig-associated co-receptors, Ig-alpha and Ig-beta. The nature of the cyclin:cdk complexes that are targeted by anti-Mu will be determined using elutriator purified G1 lymphoma cells. In addition, E2F, which is bound by pRb, will be over-expressed to determine whether cell cycle arrest is required for induction of apoptosis. The effect of anti-mu on localization and activity of myc will be studied based on the idea that this molecule plays a critical role in the balance between cell cycle progression and apoptosis. Finally, the points at which T-cell signals interfere with apoptosis-inducing signals with be examined, since these can prevent anti-Mu induced apoptosis in these lymphomas. The results of these studies will provide information on regulation of neoplastic growth as well as mechanism for inducing apoptosis in a model for deletional tolerance.
Status | Finished |
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Effective start/end date | 1/05/92 → 30/04/02 |
Funding
- National Cancer Institute: $76,973.00
- National Cancer Institute: $290,979.00
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