The tumor suppressor p53 is often referred to as "the guardian of the genome" 
because of its central role in the cellular response to oncogenic stress and 
prevention of tumor development. Mutations of p53 in acute myeloid leukemia 
(AML) are rare but resistance to chemotherapy has been reported because of the 
deregulation of the p53 signaling and differentiation pathways. It is known that 
the interaction of the vitamin D metabolite 1,25-dihydroxyvitamin D(3) (1,25D) 
with its functional vitamin D receptor leads to differentiation, G(1) arrest, 
and increased cell survival in p53-null AML cells. However, there are no reports 
on the effect of 1,25D in leukemia cells expressing wild-type p53. Here, we 
examine vitamin D signaling in AML cells MOLM-13 and OCI-AML3 expressing 
wild-type p53 in the presence and absence of the MDM2 antagonist nutlin-3. We 
find that 1,25D alone induces monocytic differentiation in these cell lines 
similar to that seen in p53-null AML cells, suggesting that the presence of 
wild-type p53 is compatible with activation of vitamin D signaling. Combination 
of nutlin-3a with 1,25D accelerated programmed cell death, likely because of 
enhanced nutlin-induced upregulation of the proapoptotic PIG-6 protein and 
downregulation of antiapoptotic BCL-2, MDMX, human kinase suppressor of Ras 2, 
and phosphorylated extracellular signal-regulated kinase 2.