Contact Information: Email: email@example.com; Phone: 607-253-3354
Grant Number: 1R01CA152870-01A1
Title: Mechanism of Action of Retinoic Acid Using CD38
Annual Direct Cost: $207,500
Project Period: 07/01/2011-06/30/2016
DESCRIPTION (provided by applicant): This is a multi-investigator proposal to study a novel means of enhancing the mechanism by which retinoic acid (RA) causes growth arrest and differentiation by exploiting RA-induced expression and signaling by the CD38 receptor. RA is a cancer chemopreventive agent. It is a prohormone provided in the diet and is a common dietary insufficiency. RA can convert immature neoplastically transformed cells to a mature differentiated phenotype. The proposed studies utilize immature, uncommitted human leukemia granulocytic-monocytic precursor cells which undergo G0 arrest and either myeloid or monocytic differentiation when treated with RA or vitamin D3 (D3) respectively. RA causes activation of MAPK signaling in the process of inducing terminal myeloid differentiation/G0 arrest. Surveys of RA-induced gene expression from our and other laboratories revealed that CD38 is the earliest known receptor induced by RA. Crippling RA-induced CD38 expression cripples RA-induced differentiation, and ectopic over expression of CD38 enhances RA-induced differentiation. CD38 could potentially function through either ectoenzyme activity or receptor signaling to support differentiation: (1) The ectoenzyme activity catalyzes production of ADPR from NAD; and cADPR is able to mobilize calcium, a known regulator of differentiation and proliferation. (2) CD38 is also capable of dimerizing, which is another well known initiator of MAPK signaling. (3) CD38 has a cytosolic tail capable of binding to MAPK signaling molecules, in particular the c-Cbl adaptor. The proposed studies focus on the potential role of these functions in effecting the cellular outcome attributed to RA, namely differentiation and G0 cell cycle arrest. The proposed goals are to use small molecule probes that bind CD38, CD38 mutants, and X-ray crystallographic structures to characterize the mechanism by which CD38 promotes cell differentiation and arrest.