http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Haines, Brian B.,Ryu, Chun Jeih,Chang, Sandy,Protopopov, Alexei,Luch, Andreas,Kang, Yun Hee,Draganov, Dobrin D.,Fragoso, Maria F.,Paik, Sang Gi,Hong, Hyo Jeong,DePinho, Ronald A.,Chen, Jianzhu Cell Press 2006 CANCER CELL Vol.9 No.2
<P><B>Summary</B></P><P>Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR β gene enhancer (Eβ) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the Eβ mutation into <I>p53<SUP>−/−</SUP></I> mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1–A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.</P>
Kim, Tae-Kyung,Lee, Joong-Seob,Oh, Se-Yeong,Jin, Xun,Choi, Yun-Jaie,Lee, Tae-Hoon,Lee, Eun ho,Choi, Young-Ki,You, Seungkwon,Chung, Yong Gu,Lee, Jang-Bo,DePinho, Ronald A.,Chin, Lynda,Kim, Hyunggee American Association for Cancer Research 2007 Cancer Research Vol.67 No.23
<P>IFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PML-promoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference-mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression.</P>
FoxO1 regulates leptin-induced mood behavior by targeting tyrosine hydroxylase
Son, Dong Hwee,Doan, Khanh V.,Yang, Dong Joo,Sun, Ji Su,Kim, Seul Ki,Kang, Namju,Kang, Jung Yun,Paik, Ji-Hye,DePinho, Ronald A.,Choi, Yun-Hee,Shin, Dong Min,Kim, Ki Woo Elsevier 2019 clinical and experimental Vol.91 No.-
<P><B>Abstract</B></P> <P><B>Purpose</B></P> <P>While leptin has been associated with various psycho-physiological functions, the molecular network in leptin-mediated mood regulation remains elusive.</P> <P><B>Methods</B></P> <P>Anxiolytic behaviors and tyrosine hydroxylase (TH) levels were examined after leptin administration. Functional roles of STAT3 and FoxO1 in regulation of TH expression were investigated using in vivo and in vitro systems. A series of animal behavioral tests using dopaminergic neuron-specific FoxO1 KO (FoxO1 KO<SUP>DAT</SUP>) were performed and investigated the roles of FoxO1 in regulation of mood behaviors.</P> <P><B>Results</B></P> <P>Here, we show that administration of leptin induces anxiolytic-like phenotype through the activation of signal transducer and activator of transcription 3 (STAT3) and the inhibition of forkhead box protein O1 (FoxO1) in dopaminergic (DA) neurons of the midbrain. Specifically, STAT3 and FoxO1 directly bind to and exert opposing effects on tyrosine hydroxylase (TH) expression, where STAT3 acts as an enhancer and FoxO1 acts as a prominent repressor. Accordingly, suppression of the prominent suppressor FoxO1 by leptin strongly increased TH expression. Furthermore, our previous results showed that specific deletion of FoxO1 in DA neurons (FoxO1 KO<SUP>DAT</SUP>) led to a profound elevation of TH activity and dopamine contents. Finally, FoxO1 KO<SUP>DAT</SUP> mice exhibited enhanced leptin sensitivity as well as displayed reduced anxiety- and depression-like behaviors.</P> <P><B>Conclusions</B></P> <P>This work establishes a novel molecular mechanism of mood behavior regulation by leptin and suggests FoxO1 suppression by leptin might be a key for leptin-induced behavioral manifestation in DA neurons.</P> <P><B>Highlights</B></P> <P> <UL> <LI> TH increment by leptin is via STAT3 activation and FoxO1 inhibition in midbrain. </LI> <LI> FoxO1 inhibition by leptin is a key in leptin-induced anxiolytic-like behavior. </LI> <LI> FoxO1 KO<SUP>DAT</SUP> mice showed enhanced leptin sensitivity and anxiolytic-like behavior. </LI> </UL> </P>