RESUMO
c-Jun activation domain binding protein-1 (JAB1) is a multifunctional regulator that plays vital roles in diverse cellular processes. It regulates AP-1 transcriptional activity and also acts as the fifth component of the COP9 signalosome complex. While JAB1 is considered an oncoprotein that triggers tumor development, recent studies have shown that it also functions in neurological development and disorders. In this review, we summarize the general features of the JAB1 gene and protein, and present recent updates on the regulation of JAB1 expression. Moreover, we also highlight the functional roles and regulatory mechanisms of JAB1 in neurodevelopmental processes such as neuronal differentiation, synaptic morphogenesis, myelination, and hair cell development and in the pathogenesis of some neurological disorders such as Alzheimer's disease, multiple sclerosis, neuropathic pain, and peripheral nerve injury. Furthermore, current challenges and prospects are discussed, including updates on drug development targeting JAB1.
Assuntos
Complexo do Signalossomo COP9 , Peptídeos e Proteínas de Sinalização Intracelular , Peptídeo Hidrolases , Complexo do Signalossomo COP9/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , HumanosRESUMO
Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.
RESUMO
Psoriasis, a chronic immune-mediated inflammatory skin disease, is characterized by dysregulated keratinocyte proliferation. The EF-hand calcium binding protein S100A7 has been found to be overexpressed in psoriatic keratinocytes. It is know that S100A7 may interact with Jab1, a cofactor that stabilizes c-Jun. Jab1 is known to downregulate the expression of the cell cycle inhibitor p27Kip1 in some cancer models. In this study, we aimed to investigate the possible interaction between S100A7 and Jab1 and the downstream effects on p27 Kip1 expression in normal human keratinocyte cells transfected with S100A7 CRISPR activation plasmid and in archival psoriatic skin samples. Our results showed that the upregulated S100A7 colocalizes with Jab1 at the nuclear level in transfected cells and psoriatic skin samples. We also showed a differential protein expression of Jab1 between cytoplasmic and nuclear compartments, thus suggesting Jab1 translocation from nucleus to cytoplasm. p27 Kip1 protein expression patterns would imply a translocation from nucleus and a subsequent degradation of this protein. The upregulation of S1007 and its interaction with Jab1 would contribute to the p27 Kip1 -dependent impaired proliferation that characterizes psoriatic skin.
Assuntos
Complexo do Signalossomo COP9/metabolismo , Sistemas CRISPR-Cas , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Queratinócitos/metabolismo , Peptídeo Hidrolases/metabolismo , Psoríase/metabolismo , Proteína A7 Ligante de Cálcio S100/metabolismo , Complexo do Signalossomo COP9/genética , Estudos de Casos e Controles , Núcleo Celular/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Citoplasma/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Queratinócitos/citologia , Peptídeo Hidrolases/genética , Psoríase/genética , Psoríase/patologia , Proteína A7 Ligante de Cálcio S100/antagonistas & inibidores , Proteína A7 Ligante de Cálcio S100/genéticaRESUMO
c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional protein involved in cell proliferation and apoptosis, DNA damage and repair and genome stability. In a number of types of human carcinoma, the abnormal expression of Jab1 is associated with poor prognosis, suggesting that Jab1 serves a vital function in tumorigenesis. However, the functional effects and the underlying molecular mechanisms of Jab1 in laryngeal squamous cell carcinoma (LSCC) progression remain poorly understood. The results of the present study demonstrate that downregulating Jab1 expression promotes LSCC apoptosis while inhibiting the proliferation of LSCC cells. Furthermore, Jab1 inhibition results in decreased protein kinase B phosphorylation accompanied by increased caspase-3 cleavage and p53 expression. It has been identified that the increased expression of Jab1 is markedly associated with LSCC progression, therefore Jab1 may be used as a novel target for the treatment of laryngeal cancer.
RESUMO
Overexpression of LIM and SH3 protein 1 (LASP1) is required for colorectal cancer (CRC) development and progression. Here, C-Jun activation domain-binding protein-1 (Jab1), also known as COP9 signalosome subunit 5 (COPS5), was verified as a new LASP1-interacting protein through yeast two-hybrid assay. The role of COPS5 in LASP1-mediated CRC progression remains unknown. GST pull-down assay indicated that the SH3 domain of LASP1 could directly bind to MPN domain of COPS5. In vitro gain- and loss-of-function analyses revealed the stimulatory role of COPS5 on CRC cell proliferation, migration and invasion. Endogenous overexpression of COPS5 could also enhance the homing capacity of CRC cells in vivo. Further analysis showed that COPS5 and LASP1 synergistically interact to stimulate the ubiquitination and degradation of 14-3-3σ and promote colorectal cancer progression via PI3K/Akt dependent signaling pathway. Clinically, the expression of COPS5 was studied in CRC tissues and it is associated with CRC differentiation, metastasis and poor prognosis. The colocalization of LASP1 and COPS5 was demonstrated in both nonmetastatic and metastatic CRC tissues. A positive correlation was found between the expression of LASP1 and COPS5 while a negative correlation existed between 14-3-3σ and COPS5/LASP1 in most CRC samples. A combination of COPS5 and LASP1 tends to be an independent prognostic indicator for CRC patients, and this is also suitable for CRC without lymph node metastasis. The current research has further advanced our understanding on the complicated molecular mechanism underlying LASP1-mediated CRC progression, which hopefully will contribute to the development of novel diagnostic and therapeutic strategies in CRC.
Assuntos
Proteínas 14-3-3/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/biossíntese , Complexo do Signalossomo COP9/metabolismo , Neoplasias Colorretais/metabolismo , Proteínas do Citoesqueleto/metabolismo , Exorribonucleases/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Peptídeo Hidrolases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas 14-3-3/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Biomarcadores Tumorais/genética , Complexo do Signalossomo COP9/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas do Citoesqueleto/genética , Progressão da Doença , Regulação para Baixo , Ativação Enzimática , Exorribonucleases/genética , Células HCT116 , Células HT29 , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Camundongos , Camundongos Nus , Peptídeo Hidrolases/genética , Transdução de SinaisRESUMO
The earliest stages of neuronal and sensory cell development in vertebrate sensory organs depend on "inflammatory" immune system neurotrophic cytokines/chemokines. Although classical nerve growth factors, brain-derived neurotrophic factors and glial growth factors play critical roles at various stages, the earliest directive roles belong to immune system cytokines. In frogs, fishes, birds and mammals, macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein 1 (MCP1) and RANTES, components of the otocyst-derived factor, are involved in sorting, morphogenesis, providing directional neuronal outgrowth cues as well as survival factors for both neurons and sensory cells. In this review we discuss their roles in the vertebrate inner ear.
Assuntos
Quimiocinas/metabolismo , Citocinas/metabolismo , Orelha Interna/crescimento & desenvolvimento , Orelha Interna/metabolismo , Sistema Imunitário/imunologia , Sistema Nervoso/imunologia , Animais , HumanosRESUMO
Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase, especially the rate-limiting determinant of telomerase activity. So far, TERT has been reported to be over-expressed in more than 90% of cancers, thereby playing a critical role in sustained proliferation and survival potentials of various cancer cells. Over the past decade, a comprehensive network of transcription factors has been shown to be involved in the regulation of TERT. Furthermore, accumulating evidence has suggested that TERT could modulate the expression of numerous genes involved in diverse group of cellular processes, including cell cycle regulation and cellular signaling. Therefore, it indicates that TERT is both an effector and a regulator in carcinoma. However, the mechanisms of the interaction between TERT and its target genes are still not fully understood. Thus, it is necessary to consolidate and summarize recent developments of the cross-talk between TERT and related genes in cancer cells or other cells with cancer cell characteristics, and elucidate these relevant mechanisms. In this review, we focus on various signaling pathways and genes that participate in the feedback regulation of TERT and the underlying feedback loop mechanism of TERT, further providing new insights into non-telomeric functions of telomerase and potentially to be used as a novel therapeutic target for cancer.