ERBB2 oncogenicity: ERBIN helps to perform the job.
Ontology highlight
ABSTRACT:
SUBMITTER: Mei L
PROVIDER: S-EPMC4905317 | biostudies-other | 2015 Jul-Sep
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation-mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach.
| S-EPMC3390846 | biostudies-literature
Project description:SOX9 [sex-determining region Y (SRY)-box 9 protein], a high mobility group box transcription factor, plays critical roles during embryogenesis and its activity is required for development, differentiation, and lineage commitment in various tissues including the intestinal epithelium. Here, we present functional and clinical data of a broadly important role for SOX9 in tumorigenesis. SOX9 was overexpressed in a wide range of human cancers, where its expression correlated with malignant character and progression. Gain of SOX9 copy number is detected in some primary colorectal cancers. SOX9 exhibited several pro-oncogenic properties, including the ability to promote proliferation, inhibit senescence, and collaborate with other oncogenes in neoplastic transformation. In primary mouse embryo fibroblasts and colorectal cancer cells, SOX9 expression facilitated tumor growth and progression whereas its inactivation reduced tumorigenicity. Mechanistically, we have found that Sox9 directly binds and activates the promoter of the polycomb Bmi1, whose upregulation represses the tumor suppressor Ink4a/Arf locus. In agreement with this, human colorectal cancers showed a positive correlation between expression levels of SOX9 and BMI1 and a negative correlation between SOX9 and ARF in clinical samples. Taken together, our findings provide direct mechanistic evidence of the involvement of SOX9 in neoplastic pathobiology, particularly, in colorectal cancer.
| S-EPMC3378515 | biostudies-literature
Project description:We set out to study the key effectors of resistance and sensitivity to ErbB2 tyrosine kinase inhibitors, such as lapatinib in ErbB2-positive breast and lung cancers. A cell-based in vitro site-directed mutagenesis lapatinib resistance model identified several mutations, including the gatekeeper ErbB2 mutation ErbB2-T798I, as mediating resistance. ErbB2-T798I engineered cell models indeed show resistance to lapatinib but remain sensitive to the irreversible EGFR/ErbB2 inhibitor, PD168393, suggestive of potential alternative treatment strategies to overcome resistance. Gene expression profiling studies identified a select group of downstream targets regulated by ErbB2 signaling and define PHLDA1 as an immediately downregulated gene upon oncogenic ErbB2 signaling inhibition. We find significant down-regulation of PHLDA1 in primary breast cancer and PHLDA1 is statistically significantly less expressed in ErbB2 negative compared with ErbB2 positive tumors consistent with its regulation by ErbB2. Lastly, PHLDA1 overexpression blocks AKT signaling, inhibits cell growth and enhances lapatinib sensitivity further supporting an important negative growth regulator function. Our findings suggest that PHLDA1 might have key inhibitory functions in ErbB2 driven lung and breast cancer cells and a better understanding of its functions might point at novel therapeutic options. In summary, our studies define novel ways of modulating sensitivity and resistance to ErbB2 inhibition in ErbB2-dependent cancers.
| S-EPMC4169529 | biostudies-literature
Project description:BackgroundSessional academic staff are an important part of nursing education. Increases in casualisation of the academic workforce continue and satisfaction with the job role is an important bench mark for quality curricula delivery and influences recruitment and retention. This study examined relations between four job constructs - organisation fit, organisation support, staff role and job satisfaction for Sessional Academic Staff at a School of Nursing by creating two path analysis models.MethodsA cross-sectional correlational survey design was utilised. Participants who were currently working as sessional or casual teaching staff members were invited to complete an online anonymous survey. The data represents a convenience sample of Sessional Academic Staff in 2016 at a large school of Nursing and Midwifery in Australia. After psychometric evaluation of each of the job construct measures in this study we utilised Structural Equation Modelling to better understand the relations of the variables.ResultsThe measures used in this study were found to be both valid and reliable for this sample. Job support and job fit are positively linked to job satisfaction. Although the hypothesised model did not meet model fit standards, a new 'nested' model made substantive sense.ConclusionThis small study explored a new scale for measuring academic job role, and demonstrated how it promotes the constructs of job fit and job supports. All four job constructs are important in providing job satisfaction - an outcome that in turn supports staffing stability, retention, and motivation.
| S-EPMC5968670 | biostudies-literature
Project description:Human T-cell leukemia virus-1 (HTLV-1) is the first pathogenic human retrovirus identified in 1979 by the Gallo group. HTLV-1 causes fatal T-cell leukemia (adult T cell leukemia) and a progressive myelopahy (HTLV-1-associated myelopathy/ tropical spastic paraparesis, HAM/TSP) and other disorders. Since the discovery of HTLV-1, several other microorganisms are demonstrated to cause cancer in humans. In this article, we investigated the oncogenic capacity of HTLV-1, in comparison with those of other oncoviruses and one oncobacterium (Helicobacter pylori, H. Pylori) based on published literature. We conclude here that HTLV-1 is one of the most and may be the most carcinogenic among them and arguably one of the most potent of the known human carcinogens. This fact has not been noted before and is particularly important to justify why we need to study HTLV-1 as an important model of human viral oncogenesis.
| S-EPMC5539117 | biostudies-other
Project description:CTL-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4-Tyk2-STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. Cancer Res; 77(18); 5118-28. ©2017 AACR.
| S-EPMC5600851 | biostudies-literature
Project description:OBJECTIVE:The Job Demands and Control model classifies job types as active, passive, low-strain or high-strain, based on a combination of job demands and control. While studies have shown high-strain jobs to have adverse consequences for health and work participation, prognostic factors for the four job types have been less explored. The aim of this study was to assess the associations between sociodemographic factors and job descriptors and being in high-strain, low-strain, active and passive jobs. METHODS:The WIRUS Screening study targeted Norwegian employees in private and public enterprises. In this study, associations with job types among 4,487 employees were investigated with binary logistic regression analyses, adjusting for sociodemographic and job-related variables. RESULTS:In fully adjusted models, high-strain job was associated with female gender; lower education; shift work; and doing work outside the workplace. Low-strain job was associated with opposite scores on the same variables, and with lower job position. Active job was associated with lower age; female gender; higher levels of education; higher job position level; shift work; and not doing work outside the workplace. Passive job was associated with opposite scores on the same variables. CONCLUSIONS:The study corroborates the role gender and education have for experiencing the job, and expands on existing knowledge on the role of job position and irregular working hours and spaces. By identifying factors associated with job types, the prevention of health problems and work disability may become be more targeted.
| S-EPMC6936855 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-24 | GSE211456 | GEO
Project description:The anti-ErbB2 antibodies trastuzumab and pertuzumab in combination have recently been approved for the treatment of patients with ErbB2-positive metastatic breast cancer. Pertuzumab, which binds to ErbB2 near the center of domain II, and trastuzumab, which binds to the juxtamembrane region of ErbB2 domain IV, directly interfere with domain II- and domain IV-mediated heterodimerization contacts, respectively. In this study, we report a novel anti-ErbB2 antibody, 3E10, which binds to an epitope in domain III that appears to be located opposite to the dimerization interfaces in domain II and domain IV of ErbB2. Our data show that the 3E10 antibody inhibits ErbB2 heterodimerization via a mechanism that strikingly differs from trastuzumab and pertuzumab. It could be speculated that the 3E10 antibody may affect ErbB2 heterodimerization by causing major conformational changes of ErbB2. Furthermore, 3E10 provides synergistic inhibition of ErbB2 heterodimerization and signaling in combination with either trastuzumab or pertuzumab. The combination of these three anti-ErbB2 antibodies that have complementary mechanisms of action appears to be an extremely potent ErbB2 heterodimerization blocker. Compared with trastuzumab plus pertuzumab, the combination of trastuzumab, pertuzumab and 3E10 provides a more potent blockade of ErbB2 signaling. Consistent with this, trastuzumab plus pertuzumab plus 3E10 results in greater in vitro and in vivo antitumor activity in ErbB2-overexpressing breast tumor models, suggesting its potential use for treating ErbB2-overexpressing breast cancer.
| S-EPMC4815051 | biostudies-literature