Protein-tyrosine kinases (PTKs) are important regulators of intracellular signal-transduction pathways mediating development and multicellular communication in metazoans Their activity is normally tightly controlled and regulated Perturbation of PTK signalling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation The lipid kinase phosphoinositide 3-OH kinase (PI(3)K) and some of its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70S6K), are crucial effectors in oncogenic PTK signalling This review emphasizes how oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity and provides an update on our knowledge about the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies

Oncogenic kinase signalling

Diagnosis of gastrointestinal stromal tumors: A consensus approach.

A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis ('cancer genes'). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a 'census' of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes.

A census of human cancer genes

ObjectiveTo analyze the outcome of 200 patients with gastrointestinal stromal tumor (GIST) who were treated at a single institution and followed up prospectively.Summary Background DataA GIST is a visceral sarcoma that arises from the gastrointestinal tract. Surgical resection is the mainstay of tre

https://ink.library.smu.edu.sg/cgi/viewcontent.cgi?article=1016&context=soe_research

Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival.

Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.

https://science.sciencemag.org/content/sci/279/5350/577.full.pdf

Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.

○ Background.-Psammoma bodies are often observed in papillary carcinomas of the thyroid. Recently we reported that osteopontin (OPN) appears to play an important role in the development of psammoma bodies in meningiomas. Because the morphology and components of psammoma bodies in papillary carcinoma of the thyroid are similar to those of psammoma bodies in meningioma, we examined whether OPN was related to the psammoma bodies in papillary carcinoma of the thyroid. Methods.-Expression of OPN mRNA was examined by Northern blotting and in situ hybridization. Immunohistochemistry was performed to localize the deposition of OPN protein and to identify the type of OPN mRNA-expressing cells. Results.-The expression of OPN mRNA was detected in papillary thyroid carcinomas but not in normal thyroid tissue. Osteopontin mRNA-expressing cells were present around the psammoma bodies, and the localization of OPN protein was consistent with that of psammoma bodies. The OPN mRNA-expressing cells were identified as CD68-positive macrophages. Conclusion.-Osteopontin produced by macrophages may play a significant role in the development of psammoma bodies in papillary carcinoma of the thyroid.

/pdf/possible-relation-of-osteopontin-to-development-of-psammoma-2w4gcmwjo0.pdf

Possible relation of osteopontin to development of psammoma bodies in human papillary thyroid cancer

Mast cells develop when spleen cells of mice are cultured in the medium containing interleukin (IL)-3. Cultured mast cells (CMCs) show apoptosis when they are incubated in the medium without IL-3. We obtained CMCs from tg/tg mice that did not express the transcription factor encoded by the mi gene (MITF) due to the integration of a transgene at its 5' flanking region. MITF is a member of the basic-helix-loop-helix-leucine zipper (bHLH-Zip) protein family of transcription factors. We investigated the effect of MITF on the apoptosis of CMCs after removal of IL-3. When cDNA encoding normal MITF ((+)-MITF) was introduced into tg/tg CMCs with the retroviral vector, the apoptosis of tg/tg CMCs was significantly accelerated. The mutant mi allele represents a deletion of an arginine at the basic domain of MITF. The apoptosis of tg/tg CMCs was not accelerated by the introduction of cDNA encoding mi-MITF. The overexpression of (+)-MITF was not prerequisite to the acceleration of the apoptosis, as the apoptotic process proceeded faster in +/+ CMCs than in mi/mi CMCs. The Ba/F3 lymphoid cell line is also dependent on IL-3, and Ba/F3 cells show apoptosis after removal of IL-3. The c-myc gene encodes another transcription factor of the bHLH-Zip family, and the overexpression of the c-myc gene accelerated the apoptosis of Ba/F3 cells. However, the overexpression of (+)-MITF did not accelerate the apoptosis of Ba/F3 cells. The (+)-MITF appeared to play some roles for the acceleration of the apoptosis specifically in the mast cell lineage.

/pdf/involvement-of-transcription-factor-encoded-by-the-mouse-mi-423r09kxlj.pdf

Ghulam Muhammad Tunio

Papers

Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.

Possible relation of osteopontin to development of psammoma bodies in human papillary thyroid cancer

Involvement of transcription factor encoded by the mouse mi locus (MITF) in apoptosis of cultured mast cells induced by removal of interleukin-3.