Interaction between PPAR-gamma and Retinoic Acid Receptor (RAR) pathways during the differentiation of monocytic leukemia cells

Attila Szanto
Department of Biochemistry and Molecular Biology
University of Debrecen, Medical and Health Science
Center
98 Nagyerdei krt.
DEBRECE, H-4012
telephone: +36-52-416-432
fax: +36-52-416-432
email: szantoa@indi.biochem.dote.hu
prestype: Poster
presenter: Attila Szanto

Attila Szanto and Laszlo Nagy
Department of Biochemistry and Molecular Biology, University of Debrecen, Nagyerdei krt. 98, DEBRECEN, Hungary H-4012

Both PPAR-gamma and Retinoic Acid Receptor (RAR) belong to the nuclear hormone receptor superfamily and they play a role in the differentiation of myelomonocytic cells. Activation of the RAR pathway leads to a granulocytic direction and activation of the PPAR-gamma pathway leads to monocytic differentiation. We looked for factors that determine the fate of the differentiating cells and characterized the interactions between the two pathways using methods of global transcription profiling and quantitative transcript determinations.

We used monocytic leukaemia cell lines and treated the cells with nuclear hormone receptor agonists and antagonist. We found that PPAR-gamma mRNA levels increased parallel with the degree of monocytic differentiation. Activation of either PPAR-gamma or its heterodimeric partner RXR led to inhibition of proliferation and subsequent differentiation. We monitored this process by determining the surface expression of the myeloid markers, CD14 and CD18 and several receptor target genes such as CD36, LXR-alpha (liver X receptor) for PPAR:RXR activation and CD38 and RAOH (retinoic acid hydroxilase) for RAR:RXR heterodimer activation.

We analyzed the pharmacological profile of differentiation and the mechanism of interactions between the receptor pathways and found that activation of the RAR leads to an increased expression of the PPAR-gamma target genes. This phenomenon is accompanied with an elevation of the PPAR-gamma receptor molecule number. On the other side PPAR-gamma activation leads to a decreased response of the RAR target genes. We characterized these processes and propose potential mechanism for them.