12 research outputs found
Pharmacological targeting of STK19 inhibits oncogenic NRAS driven melanomagenesis
黑色素瘤是由黑色素细胞恶性转化产生的恶性程度极高的皮肤癌,含有NRAS激活突变的黑色素瘤约占20-30%,但至今还未有靶向NRAS的有效黑色素瘤治疗方案。针对这一难题,波士顿大学医学中心崔儒涛教授、厦门大学生命科学学院邓贤明教授、复旦大学附属肿瘤医院王鹏教授组成的联合研究团队利用激酶组siRNA文库筛选发现新颖的丝/苏氨酸激酶STK19是NRAS的上游激活子,进一步分子机制研究揭示STK19通过磷酸化NRAS的89位丝氨酸(S89)促进了NRAS介导的黑色素细胞恶性转化。该研究揭示了一种经由新颖激酶STK19调控NRAS突变黑色素瘤的分子机制,验证了STK19有望作为NRAS介导的黑色素瘤的有效靶标,为发展新的黑色素瘤靶向药物提供了先导化合物,同时也为发展其它素有“癌基因之王---RAS”驱动的相关肿瘤靶向药物发展提供了新思路。该论文由波士顿大学医学中心、厦门大学生命科学学院、复旦大学附属肿瘤医院等单位合作完成,共同第一作者厦门大学生命科学学院博士生张婷负责了该系列化合物的设计、合成与优化,崔儒涛教授、邓贤明教授和王鹏教授为共同通讯作者。【Abstract】Activating mutations in NRAS account for 20-30% of melanoma, but despite decades of research and in
contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here we identify a previously
uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS
to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte
malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in
25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to
enhance melanocyte transformation. STK19 D89N knockin leads to skin hyperpigmentation and promotes
NRAS Q61R -driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific
STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte
malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new
and viable therapeutic strategy for melanomas harboring NRAS mutations.We thank Drs. Norman Sharpless and David Fisher for kindly providing the loxP/STOP/loxP NRAS Q61R
knockin (LSL-NRAS Q61R ) mice. We thank Dr. Anurag Singh for kindly sharing cell lines. We also thank
Drs. X. Shirley Liu, Tao Wang, Wantao Chen, Dali Liu, Chunxiao Xu, Jianming Zhang and Junrong Zou
for discussion and assistance. This work was supported by grants from Boston University (to R.C.), the
National Key R&D Program and the National Natural Science Foundation of China (No.
2017YFA0504504, 2016YFA0502001, 81422045, U1405223 and 81661138005 to X.D.), the
Fundamental Research Funds for the Central Universities of China (No. 20720160064 to X.D.), and the
Program of Introducing Talents of Discipline to Universities (111 Project, B12001).该研究得到了科技部重点研发计划、国家自然科学基金委和中央高校基本科研业务费等的资助
Identification of differentially expressed genes associated with the enhancement of X-ray susceptibility by RITA in a hypopharyngeal squamous cell carcinoma cell line (FaDu)
Next generation sequencing and bio-informatic analyses were conducted to investigate the mechanism of reactivation of p53 and induction of tumor cell apoptosis (RITA)-enhancing X-ray susceptibility in FaDu cells
Electrospinning Synthesis of Mesoporous MnCoNiO<sub><i>x</i></sub>@Double-Carbon Nanofibers for Sodium-Ion Battery Anodes with Pseudocapacitive Behavior and Long Cycle Life
In this work, MnCoNiO<sub><i>x</i></sub> (denoted as
MCNO) nanocrystals (with a size of less than 30 nm) finely encapsulated
in double-carbon (DC, including reduced graphene oxide and amorphous
carbon derived by polymer) composite nanofibers (MCNO@DC) were successfully
synthesized via an electrospinning method followed by a sintering
treatment. The as-obtained MCNO@DC nanofibers present superior sodium
storage performance and retain an especially high specific capacity
of 230 mAh g<sup>–1</sup> with a large capacity retention of
about 96% at 0.1 A g<sup>–1</sup> after 500 cycles and a specific
capacity of 107 mAh g<sup>–1</sup> with capacity retention
of about 89% at 1 A g<sup>–1</sup> after 6500 cycles. The outstanding
cycle characteristic is mainly due to the tiny MCNO nanoparticles,
which shorten the ion migration distance, and the three-dimensional
DC framework, which remarkably promotes the electronic transfer and
efficiently limits the volume expansion during the progress of insertion
and extraction of Na<sup>+</sup> ions. Moreover, nitrogen doped in
carbon is able to improve the electrochemical capability as well.
Finally, kinetic analysis of the redox reactions is used to verify
the pseudocapacitive mechanism in charge storage and the feasibility
of using MCNO@DC composite nanofibers as an anode for sodium-ion batteries
with the above-mentioned behavior