Pin1-mediated prolyl isomerization of Runx1 affects PU.1 expression in pre-monocytes.

Abstract

Regulation of the hematopoietic transcription factor PU.1, a member of the ETS family, plays a critical role in the development of blood cells and in leukemia. The dosage of PU.1 has been shown to cause a shift in myelomonocytic progenitor fate. Pin1 is a unique substrate-specific enzyme that can isomerize phospho-Ser/Thr-Pro peptide bonds, accelerating the conformational change in its substrates between a cis and a trans form. Such activity has been demonstrated to be a tightly controlled mechanism regulating a wide variety of protein functions under both normal physiological and pathological conditions. We have previously reported that a conformational change in Runx2 induced by Pin1 is essential for its function in osteogenesis in vitro and in vivo. In this study, we show that the Pin1-mediated conformational change in Runx1 enhances its acetylation and stabilization and, consequently, enhances its transacting activity. The increased acetylation of Runx1 represses PU.1 transcription in pre-monocytes. Conversely, the lack of (or the inhibition of) Pin1 increases PU.1 transcription in vitro and in vivo in pre-monocytes and in the spleen tissue. Pin1 KO mice have an increased CD11b(+) /F4/80(+) cell population and F4/80 protein expression in spleen. From our data, we can conclude that the conformational change in Runx1 induced by Pin1 represses PU.1 transcription in pre-monocytes and influences the commitment to the monocyte lineage. The dosage of PU.1 is a crucial factor in acute myeloid leukemia (AML), and Pin1 may thus be a useful target for controlling PU.1-dependent hematopoiesis, as well as leukemogenesis.

• Authors: Rabia Islam, Won-Joon Yoon, Kyung-Mi Woo, Jeong-Hwa Baek, Hyun-Mo Ryoo
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 229 Issue 4 Pg. 443-52 (Apr 2014) ISSN: 1097-4652 [Electronic] United States
• PMID: 24037986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Wiley Periodicals, Inc.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• NIMA-Interacting Peptidylprolyl Isomerase
• Proto-Oncogene Proteins
• RNA, Messenger
• Runx1 protein, mouse
• Trans-Activators
• proto-oncogene protein Spi-1
• PIN1 protein, human
• Peptidylprolyl Isomerase
• Pin1 protein, mouse

Topics

• Animals
• Cells, Cultured
• Core Binding Factor Alpha 2 Subunit (genetics, metabolism)
• Gene Expression Regulation (physiology)
• Humans
• Mice
• Mice, Knockout
• Monocytes (metabolism)
• NIMA-Interacting Peptidylprolyl Isomerase
• Peptidylprolyl Isomerase (genetics, metabolism)
• Protein Binding
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA, Messenger
• Trans-Activators (genetics, metabolism)