本日は "バレンタイン=デー"。欧米の習慣によれば、恋人宛てに、熱い愛の囁き (メッセージ) をカードにたくして送る日。そこで、この日に因んで、間もなく迫る国立大学入試向けの (しゃれた) 英語の出題例 (記述問題) を受験生諸君へ送ろう。
出題問題: 恋人から、Valentine Card に添えて、"I LOVE YOU" というメッセージをもらった。 この恋人に、返信すべき英語 を、Two Words で、記述せよ！
ヒント: 目下、欧米では、過去に上司から「セクハラ」などを受けた被害者 (主に女性たち) が、こぞって「 」運動を始めた。その結果、(トランプ大統領を除く) 有名な映画監督や政治家が失脚し始めた。 この 「 」 に入る Two Words が正解である。
2018年2月14日水曜日
2018年2月1日木曜日
2017 Lasker Award to Prof. Mike Hall, the Father of "TOR" (Target of Rapamycin)
Rapamycin is among antibiotics isolated by a Canadian team from a soil bacterium in Rapa, Nui, Easter Island, in 1975. Originally, its was recognized as an anti-fungal compound. However, later it was found to be a potent "immune suppressor" useful for organ transplantation. Interestingly, it has an anti-cancer activity as well. However, because of its immuno-suppressive activity, it has never been a favorable anti-cancer drug. To a big surprise, however, around 2009, Rapamycin was found by a US team led by Dr. David Harrison to extend significantly (by 9-14%) the lifespan of old (20 months) mice. Thus, it is among natural elixirs (longevity-promoters).
In 1991, a Swiss team led by Prof. Mike Hall at University of Basel (Biozentrum), identified its direct target, a kinase, in yeast. Since then, this kinase is called "target of rapamycin" (TOR), and a mammalian homolog of TOR is called mTOR. In other words, mTOR is an oncogenic/ ageing kinase, as is PAK1. Is TOR essential for melanogenesis as well, as is PAK1? According to 2016 article by a Taiwanese group, Hinokitiol (heptagonal ring compound) inhibits melano-genensis of B16F10 melanoma cells by inactivating mTOR. Thus, it is most likely that mTOR is a melanogenic kinase. The PAK1-blockers called ivermectin causes autophagy through PAK1-mTOR pathway, clearly indicating that mTOR is down-stream of PAK1.
However, according to 2012 article by a Korean group, rapamycin promotes melanogenesis, instead of suppressing it. Thus, there must be another target of rapamycin (called TOR2) in mammals, in addition to mTOR. Furthermore, KO (knock-out) of PAK1 promotes immune system, suggesting that PAK1 is immuno-suppressive, just like rapamycin. Thus, immuno-suppressive effect of rapamycin must be due to a third target called TOR3, which is not down-stream of PAK1. Therefore, for cancer therapy it would be desirable to develop a new rapamycin derivative which does not interact with TOR3.
Nevertheless, Prof. Mike Hall became a 2017 Lasker awardee. Thus, it is most likely that PAK1 pioneer(s) would also join the "Lasker Club" or "Nobel Club" in a not-distant future.
In 1991, a Swiss team led by Prof. Mike Hall at University of Basel (Biozentrum), identified its direct target, a kinase, in yeast. Since then, this kinase is called "target of rapamycin" (TOR), and a mammalian homolog of TOR is called mTOR. In other words, mTOR is an oncogenic/ ageing kinase, as is PAK1. Is TOR essential for melanogenesis as well, as is PAK1? According to 2016 article by a Taiwanese group, Hinokitiol (heptagonal ring compound) inhibits melano-genensis of B16F10 melanoma cells by inactivating mTOR. Thus, it is most likely that mTOR is a melanogenic kinase. The PAK1-blockers called ivermectin causes autophagy through PAK1-mTOR pathway, clearly indicating that mTOR is down-stream of PAK1.
However, according to 2012 article by a Korean group, rapamycin promotes melanogenesis, instead of suppressing it. Thus, there must be another target of rapamycin (called TOR2) in mammals, in addition to mTOR. Furthermore, KO (knock-out) of PAK1 promotes immune system, suggesting that PAK1 is immuno-suppressive, just like rapamycin. Thus, immuno-suppressive effect of rapamycin must be due to a third target called TOR3, which is not down-stream of PAK1. Therefore, for cancer therapy it would be desirable to develop a new rapamycin derivative which does not interact with TOR3.
Nevertheless, Prof. Mike Hall became a 2017 Lasker awardee. Thus, it is most likely that PAK1 pioneer(s) would also join the "Lasker Club" or "Nobel Club" in a not-distant future.
PAK family kinases come of age: Celebrating 40 years of discovery.
2018 Commentary to J. Cell Signal., accepted for publication (5/01/2018)
Hiroshi
Maruta, PAK Research Center, Melbourne, Australia.
e-mail: maruta20420@yahoo.co.jp
Introduction
Since our team at NIH found the very first
member of PAK family kinases (called “myosin I heavy chain kinase”) in a soil
amoeba in 1977 (1), this family of RAC/CDC42-dependent Ser/Thr kinases kept
expanding their territory during the last four decades. Among this unique family,
however, PAK1 has been most extensively studied so far, mainly because it is
essential for malignant trans-formation of mammalian cells, but non-essential
for normal cell growth (2), and shortens the healthy lifespan of small animals
such as C. elegans (3), and is
involved even in PDGF/a-MSH-dependent melanogenesis (4). For this reason, a variety of PAK1-blockers/inhibitors
have been developed or identified since the turn of this century, and some of
them such as propolis and 15K could be potentially useful for therapy of solid
tumors, promoting the longevity by suppressing a variety of other
PAK1-dependent diseases/disorders such as AD (Alzheimer’s disease),
hyper-tension and diabetes (type 2), and even for the cosmetic treatment of
hyper-pigmentation (so-called “skin-whitening”). Thus, the potential market
value of these PAK1-blockers would be huge in both pharmaceutical and cosmetic
industries. In this commentary, I shall briefly highlight the uniqueness of
PAK1-blockers useful for signaling therapy causing no serious side effect, in
contrast to conventional anti-cancer drugs such as DNA/RNA/microtubule
poisons which clearly cause serious side effects such as hair-loss, suppression
of immune system and loss of appetite. Rather surprisingly, these PAK1-blockers
such as propolis and 15K promote hair growth and boost even our immune system
(5, 6), easing the damaging side effects caused by conventional anti-cancer
drugs.
References
- Maruta H, Korn ED. Acanthamoeba cofactor protein is a heavy chain kinase (PAK) required for actin activation of the Mg2+-ATPase activity of Acanthamoeba myosin I. J Biol Chem. 1977 ; 252: 8329-8332.
- Maruta, H. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. Phytother Res. 2014 ; 28: 656-672.
- Yanase, S, Luo, Y, Maruta, H. PAK1-deficiency/down-regulation reduces brood size, activates HSP16.2 gene and extends lifespan in C. elegans. Drug Discov Ther. 2013; 7: 29-35.
- Be-Tu PT, Nguyen BC, Tawata S, Yun CY, Kim EG, Maruta H. The serum/ PDGF-dependent “melanogenic” role of the minute level of the oncogenic kinase PAK1 in melanoma cells proven by the highly sensitive kinase assay, Drug Discov. Ther. 2016. 10: 314–322.
- Nguyen BC, Taira N, Maruta H, Tawata S. Artepillin C and Other Herbal PAK1-blockers: Effects on Hair Cell Proliferation and Related PAK1-dependent Biological Function in Cell Culture. Phytother Res. 2016; 30: 120-127.
- Huynh N, Wang K, Yim M, et al. Depletion of p21-activated kinase 1 up-regulates the immune system of APC∆14/+ mice and inhibits intestinal tumorigenesis. BMC Cancer. 2017; 17: 431.
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