Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dual-specificity phosphatase PTEN/MMAC1/TEP1 has recently been identified as the tumor suppressor gene most frequently mutated and/or deleted in human tumors. Germline mutations of PTEN give rise to Cowden Disease (CD), an autosomal dominantly-inherited cancer syndrome which predisposes to increased risk of developing breast and thyroid tumors. However, PTEN mutations have rarely been detected in sporadic thyroid carcinomas. In this study, we confirm that PTEN mutations in sporadic thyroid cancer are infrequent as we found one point mutation and one heterozygous deletion of PTEN gene in 26 tumors and eight cell lines screened. However, we report that PTEN expression is reduced both at the mRNA and at the protein level - in five out of eight tumor-derived cell lines and in 24 out of 61 primary tumors. In most cases, decreased PTEN expression is correlated with increased phosphorylation of the PTEN-regulated protein kinase Akt/PKB. Moreover, we demonstrate that PTEN may act as a suppressor of thyroid cancerogenesis as the constitutive re-expression of PTEN into two different thyroid tumor cell lines markedly inhibits cell growth. PTEN-dependent inhibition of BrdU incorporation is accompanied by enhanced expression of the cyclin-dependent kinase inhibitor p27kip1 and can be overcome by simultaneous co-transfection of an excess p27kip1 antisense plasmid. Accordingly, in a subset of thyroid primary carcinomas and tumor-derived cell lines, a striking correlation between PTEN expression and the level of p27kip1 protein was observed. In conclusion, our findings demonstrate that inactivation of PTEN may play a role in the development of sporadic thyroid carcinomas and that one key target of PTEN suppressor activity is represented by the cyclin-dependent kinase inhibitor p27kip1.
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PMID:PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27kip1. 1091 69

In chronic myelogenous leukemia (CML), hematopoietic stem cell transformation leads to increased proliferation of malignant myeloid progenitors. The cyclin-dependent kinase inhibitor p27kip1 (p27) is a critical negative regulator of hematopoietic progenitor proliferation and pool size that is deregulated in BCR-ABL expressing cell lines. However, cell-context specific regulation of p27 in primary human CML progenitors and its contribution to CML progenitor expansion remain unclear. Here, we investigated p27 regulation and function in (1) CD34+ cells from CML patients and (2) human CD34+ cells ectopically expressing the BCR-ABL gene following retrovirus transduction. We found that p27 levels are increased in CML CD34+ cells related to a BCR-ABL-dependent increase in p27 protein translation. However, p27 was relocated to the cytoplasm in CML progenitors and nuclear p27 levels were reduced, allowing increased cell cycling and expansion in culture. Cytoplasmic relocation of p27 in CML progenitors was related to signaling through BCR-ABL Y177, activation of the AKT kinase and phosphorylation of p27 on Thr-157 (T157). Expression of a mutant p27 that cannot be phosphorylated on T157 significantly inhibited CML progenitor proliferation. These studies show the importance of BCR-ABL-Y177-AKT-mediated p27 phosphorylation in altered p27 localization and enhanced proliferation and expansion of primary CML progenitors.
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PMID:Role of BCR-ABL-Y177-mediated p27kip1 phosphorylation and cytoplasmic localization in enhanced proliferation of chronic myeloid leukemia progenitors. 2020 May 61