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Lung
Published in Victor A. Bernstam, Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
The jun gene has a role as a mediator of growth factor or tumor promoter action on transcription. In about 25% of cell lines derived from different types of lung cancer, the level of jun A expression has been found markedly elevated. A related protooncogene, junB, is expressed to high levels in all the tumor cell lines studied, and, like junA, it is expressed to high levels in normal lung. The high level of expression is due to transcriptional activation.
Proto-Oncogene and Onco-Suppressor Gene Expression
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The c-jun-like genes jun-B and jun-D are functionally important members of the jun gene family.234-236 These two genes were first identified by screening of cDNA libraries prepared from serum-stimulated NIH/3T3 cells. The tissue distribution and levels of expression of the members of the jun family may be different. Whereas jun-B behaves like c-jun in relation to its high inducibility by serum and may be considered as an immediate-early gene in the mitogenic response, jun-D is already expressed in serum-starved mouse fibroblasts and is not stimulated by the addition of serum. Both c-jun and jun-B are developmentally regulated in the immature and mature mouse testis.237 Expression of the c-jun and jun-B genes is increased after dissociation of spermatogenic cells, with maximal induction in prepuberal animals. Differential expression of the genes c-jun and jun-B is observed in some types of cells, for example, in TGF-α-stimulated BC3H1 muscle cells.238 The physiological activities of c-Jun and Jun-B have been found to differ in several aspects, such as in their ability to activate AP-1 responsive genes.239 In general, Jun-B is much less active than c-Jun for its gene trans-activation and cellular transformation abilities, and these differences depend on only a few amino acid differences within the conserved DNA-binding domain of the two proteins.240 In some systems, the Jun-B protein may function as a negative regulator of c-jun gene expression.
Non-melanoma skin cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Stephen L. Morris, Sean Whittaker, Margaret Spittle
In CTCL no disease-specific balanced translocations have yet been identified but molecular cytogenetic studies do indicate that MF and SS have a closely related pattern of chromosomal abnormalities, suggesting that the two conditions share a similar if not identical pathogenesis.178,179 Numerical rather than structural abnormalities predominate, with losses of 1p, 10q, 13q, 17p and gains of 4, 17q and 18 common.180–182 As for other haematological malignancies, inactivation of cell cycle and apoptosis genes is common in MF/SS and is probably partly due to a ‘mutator phenotype’ associated with microsatellite instability due to hypermethylation of mismatch repair gene promoter sequences.183–187 Promoter hypermethylation and repression of gene transcription appears to be a common mechanism of gene inactivation in CTCL.188 Chromosomal amplification of JUNB at 19p12 has also been detected in MF/SS.189 JunB is part of the AP1 transcription factor complex involved in control of cell proliferation, differentiation and apoptosis and over-expression of JunB is likely to be the explanation for the Th2 cytokine profile commonly seen in CTCL. cDNA array studies in SS have identified a gene signature that appears to confer a worse prognosis and have also shown over-expression of a tyrosine kinase receptor, EphA4.190,191 Similar studies in MF have shown evidence for dysregulation of TNF signalling pathways.192 The signal transducers and activators of transcription (STAT) family of transcription factors are critically involved in regulating T-cell activation and, as for other solid and haematological malignancies, constitutive expression of Stat3 protein has been found in MF/SS.193 Interestingly it has been shown that EphA4 activates the Janus kinase (JAK) STAT downstream signalling pathway, which might explain the constitutive expression of Stat3 in CTCL, but this has yet to be confirmed. There is also evidence for expression of a truncated Stat5 protein in SS due to the presence of a serine protease, a situation mirrored in unactivated T-cells.194 Both early and late stages of T-cell activation may be further perturbed as there is evidence for hypermethylation of the phosphoty-rosine phosphatase (SHP-1) promoter.195 These varied and complex abnormalities have a wide variety of potential consequences, but a unifying hypothesis would be that there is dysregulation of T-cell activation in MF/SS, which prevents activation induced T-cell death.
Regulation of T cell differentiation by the AP-1 transcription factor JunB
Published in Immunological Medicine, 2021
Takaharu Katagiri, Hideto Kameda, Hiroyasu Nakano, Soh Yamazaki
JunB, a component of the transcription factor activator protein-1 (AP-1), was first identified in 1990 and is known to exhibit various physiological functions [1]. It forms dimeric AP-1 with the Fos and basic leucine zipper ATF-like transcription factor (BATF) family proteins through the basic leucine zipper (bZIP) region and regulates the expression of target genes [2]. Studies with systemic Junb-deficient and tissue-specific Junb-deficient mice revealed the important role of this protein in placentation, bone formation, maintenance of skin homeostasis, and regulation of bone marrow cell proliferation [3–6]. However, the function of JunB in the acquired immune system is yet unknown. In 2017, we along and two other research groups revealed the importance of JunB in the differentiation of T helper type 17 (Th17) cells, defined as interleukin (IL)-17-producing CD4+ T cells [7–9].
Analysis of single-cell sequencing results of an elderly patient with myeloid leukemia reveals high expression of multiple oncogenes in monocytes and hematopoietic stem cells
Published in Hematology, 2023
Xiaoli Xu, Minjian Xiong, Haiyan Ye, Yonglei Qi, Ying Zhao
Other differentially expressed genes (DEGs) closely associated with hematological malignancies have the potential to impact the development of treatment strategies for patients. The protein-coding genes JUN and JUNB, which are subunits of the AP-1 transcription factor, have been linked to hematological malignancies like primary cutaneous T-cell lymphoma and anaplastic large cell lymphoma [32, 33]. Our study revealed significantly higher expression of JUNB in monocytes and JUN in hematopoietic stem cells (HSCs) within the bone marrow compared to peripheral blood. JUN is a protein-coding gene, which can induce oncogenic transformation [34]. JUNB is located in the nucleoplasm and is involved in the positive regulation of transcription by RNA polymerase II [33]. As AML is a heterogeneous cancer, Romine et al.’s investigation delved into the sensitivity of bromodomain and extra-terminal domain inhibitors (BETi) using the Beat AML functional genomic dataset. They conducted genome-wide CRISPR screens on BETi-sensitive and BETi-resistant AML cells, finding that both methods identified SPI1, JUNB, FOS, and aryl-hydrocarbon receptor signaling (AHR/ARNT) as regulators of monocytic differentiation and determinants of the BETi response. Consequently, monocytic AML patients may exhibit greater sensitivity to BETi and venetoclax therapy [35]. Moreover, JUNB was identified as a direct target of microRNA-149*, which is highly expressed in leukemia cells. MicroRNA-149* may act as an oncogenic regulator in T-cell acute lymphoblastic leukemia by negatively regulating JUNB [36]. This focus on JUNB could potentially serve as a promising treatment strategy for AML.
Securinine Induces Differentiation of Human Promyelocytic Leukemic HL-60 Cells through JNK-Mediated Signaling Pathway
Published in Nutrition and Cancer, 2022
Jeetesh Sharma, Ankita Pandey, Sapna Sharma, Aparna Dixit
Mitogen-activated protein kinases (MAP kinases) regulate multiple aspects of cell functions, including proliferation, differentiation, and apoptosis. The signaling pathways involving c‑Jun N‑terminal kinase (JNK), and extracellular signal‑regulated kinase (ERK) were found to be critical for HL‑60 cells differentiation by securinine. These observations are in line with other reports in different leukemic cells such as U937 and HL-60 cells showing persistent ERK activation during induction of differentiation in response to various inducers and monocytic maturation (61). Our results are also in agreement with the earlier reports on ERK1 knock out mice, wherein a slight increase in the myeloid progenitor cell population with a concomitant decrease in granulocyte-monocyte progenitor cell population was noted (48, 59). The MEK-ERK signaling cascade systematically activates PU.1, which results in the downregulation of C/EBP-α (55) and C/EBP-β (68). In line with these, we observed a significant increase in the phosphorylation levels of ERK1/2 post-securinine-treatment. Increased levels of JNK upon securinine treatment as established in kinase antibody array analysis correlates well with the simultaneous increase in differentiated HL-60 cells in the present study, as inhibition of JNK has been reported to decrease monocytic differentiation of HL-60 cells by Vitamin D3 (54, 68). Recent reports on JNK activation in positive regulation of autophagy, which is essential for maturation and survival of differentiating primary human blood monocytes, further support our observation of its activation in securinine-induced differentiation. JNK, also termed as stress-activated protein kinases, are crucial signaling proteins affecting myelopoiesis and monopoiesis. JNK can be activated by a number of cytokines (eg., CSF-1, GM-CSF, TNF-α, and IL-1) and many forms of environmental stress. Mechanistically, JNK activity contributes to differentiation by activating transcription factors of the AP-1 family, especially c-Jun, JunB, and JunD (65). JNK eventually phosphorylate the PU.1 transcription factor that is essential for monocytic maturation. Thus, our results provide an insight into one of the possible mechanisms(s) involved in securinine-induced differentiation of HL-60 cells and that the securinine induces terminal differentiation of HL-60 cells to monocytes through the JNK-ERK signaling axis.