Person: Tsai, Cheng-Yu
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Tsai
First Name
Cheng-Yu
Name
Tsai, Cheng-Yu
4 results
Search Results
Now showing 1 - 4 of 4
Publication Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways(BioMed Central, 2018) Lian, Xiaolan; Lin, Yu-Min; Kozono, Shingo; Herbert, Megan K.; Li, Xin; Yuan, Xiaohong; Guo, Jiangrui; Guo, Yafei; Tang, Min; Lin, Jia; Huang, Yiping; Wang, Bixin; Qiu, Chenxi; Tsai, Cheng-Yu; Xie, Jane; Cao, Ziang Jeff; Wu, Yong; Liu, Hekun; Zhou, Xiaozhen; Lu, Kunping; Chen, YuanzhongBackground: The increasing genomic complexity of acute myeloid leukemia (AML), the most common form of acute leukemia, poses a major challenge to its therapy. To identify potent therapeutic targets with the ability to block multiple cancer-driving pathways is thus imperative. The unique peptidyl-prolyl cis-trans isomerase Pin1 has been reported to promote tumorigenesis through upregulation of numerous cancer-driving pathways. Although Pin1 is a key drug target for treating acute promyelocytic leukemia (APL) caused by a fusion oncogene, much less is known about the role of Pin1 in other heterogeneous leukemia. Methods: The mRNA and protein levels of Pin1 were detected in samples from de novo leukemia patients and healthy controls using real-time quantitative RT-PCR (qRT-PCR) and western blot. The establishment of the lentiviral stable-expressed short hairpin RNA (shRNA) system and the tetracycline-inducible shRNA system for targeting Pin1 were used to analyze the biological function of Pin1 in AML cells. The expression of cancer-related Pin1 downstream oncoproteins in shPin1 (Pin1 knockdown) and Pin1 inhibitor all-trans retinoic acid (ATRA) treated leukemia cells were examined by western blot, followed by evaluating the effects of genetic and chemical inhibition of Pin1 in leukemia cells on transformed phenotype, including cell proliferation and colony formation ability, using trypan blue, cell counting assay, and colony formation assay in vitro, as well as the tumorigenesis ability using in vivo xenograft mouse models. Results: First, we found that the expression of Pin1 mRNA and protein was significantly increased in both de novo leukemia clinical samples and multiple leukemia cell lines, compared with healthy controls. Furthermore, genetic or chemical inhibition of Pin1 in human multiple leukemia cell lines potently inhibited multiple Pin1 substrate oncoproteins and effectively suppressed leukemia cell proliferation and colony formation ability in cell culture models in vitro. Moreover, tetracycline-inducible Pin1 knockdown and slow-releasing ATRA potently inhibited tumorigenicity of U937 and HL-60 leukemia cells in xenograft mouse models. Conclusions: We demonstrate that Pin1 is highly overexpressed in human AML and is a promising therapeutic target to block multiple cancer-driving pathways in AML. Electronic supplementary material The online version of this article (10.1186/s13045-018-0611-7) contains supplementary material, which is available to authorized users.Publication Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae(Nature Publishing Group UK, 2017) Albayram, Onder; Kondo, Asami; Mannix, Rebekah; Smith, Colin; Tsai, Cheng-Yu; Li, Chenyu; Herbert, Megan K.; Qiu, Jianhua; Monuteaux, Michael; Driver, Jane; Yan, Sandra; Gormley, William; Puccio, Ava M.; Okonkwo, David O.; Lucke-Wold, Brandon; Bailes, Julian; Meehan, William; Zeidel, Mark; Lu, Kun Ping; Zhou, XiaoTraumatic brain injury (TBI) is characterized by acute neurological dysfunction and associated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. We previously showed that cis phosphorylated tau (cis P-tau), but not the trans form, contributes to tau pathology and functional impairment in an animal model of severe TBI. Here we found that in human samples obtained post TBI due to a variety of causes, cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Using mouse models of severe or repetitive TBI, we showed that cis P-tau elimination with a specific neutralizing antibody administered immediately or at delayed time points after injury, attenuates the development of neuropathology and brain dysfunction during acute and chronic phases including CTE-like pathology and dysfunction after repetitive TBI. Thus, cis P-tau contributes to short-term and long-term sequelae after TBI, but is effectively neutralized by cis antibody treatment.Publication Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration(BioMed Central, 2016) Albayram, Onder; Herbert, Megan K.; Kondo, Asami; Tsai, Cheng-Yu; Baxley, Sean; Lian, Xiaolan; Hansen, Madison; Zhou, Xiao; Lu, Kun PingOne of the two common hallmark lesions of Alzheimer’s disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau, cis p-tau and trans p-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing between cis and trans isoforms of p-tau (cis p-tau and trans p-tau, respectively), cis p-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robust cis p-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably, cis p-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly, cis p-tau monoclonal antibody treatment not only eliminates cis p-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus, cis p-tau is an early driver of tau pathology in TBI and CTE and detection of cis p-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of the cis p-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE.Publication The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation(Nature Publishing Group UK, 2018) Nechama, Morris; Kwon, Jeahoo; Wei, Shuo; Kyi, Adrian Tun; Welner, Robert S.; Ben-Dov, Iddo Z.; Arredouani, Mohamed S.; Asara, John; Chen, Chun-Hau; Tsai, Cheng-Yu; Nelson, Kyle F.; Kobayashi, Koichi S; Israel, Elliot; Zhou, Xiao; Nicholson, Linda K.; Lu, Kun PingInterleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The prolyl cis-trans isomerase PIN1 is known to induce cytokines for eosinophil survival and activation by stabilizing cytokines mRNAs, but the function of PIN1 in upstream signaling pathways in asthma is unknown. Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling. Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. Thus, the IL-33-PIN1-IRAK-M is an axis critical for dendritic cell activation, type 2 immunity and IL-33 induced airway inflammation.