PTEN since its identification has been in large associated with the control of human malignancies. The dominance of PTEN over the PI3K signaling cascade is mainly
responsible for rendering it the tumor suppressive role that results in the control of a wide array of physiological processes; growth, apoptosis, proliferation and migration. However, in recent years, PTEN has expanded its TENtacles in regulating processes like stem cell
population maintenance, genomic stability regulation and activation of ovarian follicle. Meanwhile, PTEN protein phosphatase activity has gained significant importance and is even capable of inhibiting cell migration irrespective of the Akt pathway. As a protein phosphatase, it targets among others SRC kinases, CREB in the nucleus thereby regulating migration of glioma cells. Crucial for PTEN to be able to render its functions properly is the
ability to translocate to different sub-cellular compartments of the cell and even out of it
through exosomes while retaining its phosphatase activity in the cells where it is internalized. Justifiably, PTEN has fast attained the stature of one of the prime regulators of the cell and therefore it needs to be subjected to intricate surveillance. Although, PTEN like other major players of the cell shows regulation at the transcriptional level as well as through epigenetic silencing, post-translational modifications of PTEN and
the associated localization based alterations in its activities have been the focal point of research on PTEN regulatory events. There have been reports that suggest for negligible PTEN expression although the transcript levels seemed to be good enough. Thus, this study aims to delineate the post-translational modulations of PTEN and their implication in cancer. The first two parts of the work provide insights into the post-translational
regulation of PTEN mainly by ubiquitination and ubiquitination-phosphorylation crosstalk. While in the third part, a strategy to stabilize PTEN has been established through an exosomes-mediated delivery of the intrinsic C-terminus domain of PTEN that causes tumor
inhibition. In the first part of the study, we show that CHIP, the chaperone-associated E3 ligase induces ubiquitination and proteasomal degradation of PTEN as well as regulates the turnover of the protein. It was apparent from our findings that PTEN transiently associates
with the molecular chaperones and thereby gets diverted to the degradation pathway through its interaction with CHIP. The TPR domain of CHIP and parts of the N-terminal
domain of PTEN are required for their interaction. Overexpression of CHIP leads to elevated ubiquitination and a shortened half-life of endogenous PTEN. On the other hand,
depletion of endogenous CHIP stabilizes PTEN. CHIP is also shown to regulate PTENdependent transcription presumably through its downregulation. PTEN shared an inverse
correlation with CHIP in human prostate cancer patient samples thereby triggering the prospects of a more complex mode of PTEN regulation in cancer.PTEN mutation is a frequent feature across a plethora of human cancers, the hot-spot being its C-terminus (CT) regulatory domain resulting in a much diminished level of protein expression. In the second part of the work, the presence of C-terminus mutations was confirmed through sequencing of different human tumor samples. CKII-mediated phosphorylation of PTEN at these sites makes it a loopy structure competing with the E3 ligases for binding to its lipid anchoring C2 domain. Accordingly, it was found that PTEN-CT
expressing stable cell lines could inhibit tumorigenesis in syngenic breast tumor mice models. The third part shows the strategy to design a novel exosome-mediated delivery of the
intrinsic PTEN domain, PTEN-CT into different cancer cells and observed reduced proliferation, migration and colony forming ability. The delivery of exosome containing
PTEN-CT to breast tumor mice model was found to result in significant regression in tumor size with the tumor sections showing increased apoptosis. Here, we also report for the first time an active PTEN when its C2 domain is bound by PTEN-CT, probably rendering its antitumorigenic
activities through the protein phosphatase activity. Therefore, therapeutic interventions that focuses on PTEN E3 ligase inhibition through exosome-mediated PTENCT
delivery can be a probable route in the treatment of cancers with low PTEN expression. Altogether, the findings emanating from this research work could be useful in designing therapeutic strategies against cancers showing low or negligible PTEN expression.
Background: Lung hamartomas are rare tumours with compressive effects on lung parenchyma and bronchi. This is a report of our experience in the management of this condition.Methods: We retrospectively studied the records of patients with lung hamartomas managed at Alexandria University Hospital between 2001 and 2007. Information on presentation, treatment and outcome were obtained.Results: Five patients aged 35.6+14.4 years had lung hamartoma. Two patients were asymptomatic, 2 had cough and 1 presented with haemoptysis. Pre-operative diagnosis was lung carcinoma in 4 patients. Four patients had lobectomy while 1 had wedge resection. Histology confirmed fibrochondromatous hamartomas in all patients.Conclusion: Lung hamartomas should be a consideration in solitary coin lesions.Keywords: Lung hamartomas, benign tumours, lung carcinoma.
Casitas B-lineage lymphoma (Cbl or c-Cbl) is a RING ubiquitin ligase that negatively regulates protein tyrosine kinase (PTK) signalling. Phosphorylation of a conserved residue (Tyr371) on the linker helix region (LHR) between the substrate-binding and RING domains is required to ubiquitinate PTKs, thereby flagging them for degradation. This conserved Tyr is a mutational hotspot in myeloproliferative neoplasms. Previous studies have revealed that select point mutations in Tyr371 can potentiate transformation in cells and mice but not all possible mutations do so. To trigger oncogenic potential, Cbl Tyr371 mutants must perturb the LHR-substrate-binding domain interaction and eliminate PTK ubiquitination. Although structures of native and pTyr371-Cbl are available, they do not reveal how Tyr371 mutations affect Cbl's conformation. Here, we investigate how Tyr371 mutations affect Cbl's conformation in solution and how this relates to Cbl's ability to potentiate transformation in cells. To explore how Tyr371 mutations affect Cbl's properties, we used surface plasmon resonance to measure Cbl mutant binding affinities for E2 conjugated with ubiquitin (E2–Ub), small angle X-ray scattering studies to investigate Cbl mutant conformation in solution and focus formation assays to assay Cbl mutant transformation potential in cells. Cbl Tyr371 mutants enhance E2–Ub binding and cause Cbl to adopt extended conformations in solution. LHR flexibility, RING domain accessibility and transformation potential are associated with the extent of LHR-substrate-binding domain perturbation affected by the chemical nature of the mutation. More disruptive mutants like Cbl Y371D or Y371S are more extended and the RING domain is more accessible, whereas Cbl Y371F mimics native Cbl in solution. Correspondingly, the only Tyr371 mutants that potentiate transformation in cells are those that perturb the LHR-substrate-binding domain interaction. c-Cbl's LHR mutations are only oncogenic when they disrupt the native state and fail to ubiquitinate PTKs. These findings provide new insights into how LHR mutations deregulate c-Cbl.
Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.
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