京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19171号 / 医博第4013号 / 新制||医||1010(附属図書館) / 32163 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 柳田 素子, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

As the primary antagonist to the tumorigenic PI3K/AKT pathway, PTEN is classified as a tumor suppressor. The inactivation of PTEN through genetic or post-translational modifications is a critical step in the tumorigenesis of many breast cancers (BCs). SIPL1 is a novel protein which was identified as a PTEN negative regulator. To further explore SIPL1-mediated PTEN inactivation, we analyzed 17 datasets covering 3484 BC cases and 228 normal individuals. SIPL1 gene amplification and increased mRNA expression correlates with the progression and poor prognosis of ER and/or PR positive tumors. Furthermore, examination of a BC tissue microarray containing 224 tumor cases revealed elevated SIPL1 protein expression in ER+ and PR+ tumors and was associated with greater AKT activation. Additionally, ectopic expression of SIPL1 in CHO-K1 cells resulted in increased AKT activation and cell proliferation, and cytoskeleton reorganization alongside with PTEN downregulation. SIPL1 contributes to the linear polyubiquitination of NEMO, suggesting a role for SIPL1 in PTEN ubiquitination. Indeed, it was SIPL1, not the SIPL1-∆UBL (a PTEN-binding defective mutant) which robustly induced PTEN polyubiquitination in a lysine (K) 63-dependent but K48-independent manner. While K48-linked polyubiquitin chains direct protein degradation, K63-linked chains regulate a variety of protein functions. SIPL1 binds polyubiquitinated PTEN with significantly higher affinity than non-ubiquitinated PTEN. A SIPL1 mutant, SIPL1-TFLV, is unable to cause PTEN ubiquitination but is capable of PTEN association. Collectively, our results reveal that SIPL1 interacts with PTEN with a low affinity, which results in PTEN polyubiquitination, and that the modification may stabilize the association between SIPL1 and PTEN. We propose a model where SIPL1 mediates the K63-linked ubiquitination of PTEN inactivating it. The downregulation of PTEN, when paired with the tumor-promoting effects of ER and/or PR, stimulates breast tumorigenesis. SIPL1 is an important BC marker and future research should focus on its potential as a therapeutic target. / Thesis / Doctor of Philosophy (PhD)

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Atherosclerosis is an inflammatory disease in which an accumulation of fatty acids and cholesterol occurs to form a plaque in small and large arteries. Monocyte polarization to classic M1 macrophages or alternative M2 macrophages is an important area of research that can determine the severity of disease progression. BMP-7 is a key growth factor responsible for directing differentiation of mesenchymal stem cells into brown fat cells, suggesting a role of BMP-7 in cellular plasticity; however, its role in monocyte polarization is yet to be revealed. In the current study, we hypothesize that monocyte treatment with BMP-7 will significantly result in increased polarization of monocytes into M2 macrophages and increased expression of anti-inflammatory cytokines. To that effect, we have established a stress induced cell culture system with monocytes (THP-1 cells) and apoptotic conditioned medium (ACM), simulating injury, to understand the effects of BMP-7 on M2 macrophage polarization from monocytes. Our data demonstrates that the BMP type 2 receptor (BMPR2) is found on monocytes and its activation is significantly (p

Phospholipid scramblase 4 (PLSCR4) is a member of a conserved enzyme family with high relevance for the remodeling of phospholipid distribution in the plasma membrane and the regulation of cellular signaling. While PLSCR1 and -3 are involved in the regulation of adipose-tissue expansion, the role of PLSCR4 is so far unknown. PLSCR4 is significantly downregulated in an adipose-progenitor-cell model of deficiency for phosphatase and tensin homolog (PTEN). PTEN acts as a tumor suppressor and antagonist of the growth and survival signaling phosphoinositide 3-kinase (PI3K)/AKT cascade by dephosphorylating phosphatidylinositol-3,4,5-trisphosphate (PIP3). Patients with PTEN germline deletion frequently develop lipomas. The underlying mechanism for this aberrant adipose-tissue growth is incompletely understood. PLSCR4 is most highly expressed in human adipose tissue, compared with other phospholipid scramblases, suggesting a specific role of PLSCR4 in adipose-tissue biology. In cell and mouse models of lipid accumulation, we found PLSCR4 to be downregulated. We observed increased adipogenesis in PLSCR4-knockdown adipose progenitor cells, while PLSCR4 overexpression attenuated lipid accumulation. PLSCR4 knockdown was associated with increased PIP3 levels and the activation of AKT. Our results indicated that PLSCR4 is a regulator of PI3K/AKT signaling and adipogenesis and may play a role in PTENassociated adipose-tissue overgrowth and lipoma formation.

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