Interruption of p53-MDM2 Interaction by Nutlin-3a in Human Lymphoma Cell Models Initiates a Cell-Dependent Global Effect on Transcriptome and Proteome Level

ABSTRACT: In most lymphomas, p53 signaling pathway is inactivated by various mechanisms independent to p53 gene mutations or deletions. In many cases, p53 function is largely regulated by alterations in the protein abundance levels by the action of E3 ubiquitin-protein ligase MDM2, targeting p53 to proteasome-mediated degradation. In the present study, an integrating transcriptomics and pro-teomics analysis was employed to investigate the effect of p53 activation by a small-molecule MDM2-antagonist, nutlin 3a, on three lymphoma cell models following p53 activation. Our analy-sis revealed a system-wide nutlin 3a-associated effect in all examined lymphoma types, identifying in total of 4037 differentially affected proteins involved in a plethora of pathways, with significant heterogeneity among lymphomas. Our findings include known p53-targets and novel p53 activa-tion effects, involving transcription, translation, or degradation of protein components of path-ways, such as a decrease in key members of PI3K/mTOR pathway, heat-shock response, and gly-colysis, and an increase in key members of oxidative phoshosphorylation, autophagy and mito-chondrial translation. Combined inhibition of HSP90 or PI3K/mTOR pathway with nutlin 3a-mediated p53-activation enhanced the apoptotic effects suggesting a promising strategy against human lymphomas. Integrated omic profiling after p53 activation offered novel insights on the regulatory role specific proteins and pathways may have in lymphomagenesis.

INSTRUMENT(S): LTQ Orbitrap, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte

DISEASE(S): Lymphoma

SUBMITTER: Michalis Aivaliotis  

LAB HEAD: Michalis Aivaliotis

PROVIDER: PXD009290 | Pride | 2023-07-30

REPOSITORIES: Pride