31 Follicular thyroid carcinomas (FTCs) are instead characterized by activating point mutations in one of the three RAS genes (18 to 52% of cases). 25,26 In particular, papillary thyroid carcinomas (PTCs) are characterized by chromosomal rearrangements that result in the activation of the RET/PTC tyrosine kinase receptor (3 to 60% of cases), 27 by activating mutations in the gene encoding the serine/threonine kinase BRAF (28 to 69% of cases) 28–30 or by overexpression of the MET oncogene. 10 Furthermore, thyroid cancer is unique in that distinct histological features, malignant potential, and degree of differentiation can arise from a single cell and are associated with specific oncogenic lesions. In an attempt to cast light on the signaling pathways that govern loss of p27 kip1 and its cytoplasmic relocalization in human cancer, we studied thyroid follicular cell neoplasms because in these tumors p27 kip1 is inactivated by both loss of expression and cytoplasmic sequestration.
Whereas loss of p27 kip1 and its cytoplasmic relocalization in human cancer is well established, the signaling pathways that regulate these processes are primarily obscure. 7 Interaction of p27 kip1 with JAB1/CNS5 or phosphorylation of serine 10 (S10) by the hKIS kinase promotes p27 kip1 export from the nucleus, 23,24 whereas phosphorylation of threonine 157 (T157) by the protein kinase B/AKT (AKT) impairs its import. 20–22 Cytoplasmic retention of p27 kip1 may occur through increased export or reduced import. Loss of p27 kip1 expression in cancer primarily occurs through sustained protein degradation, 15–17 a four-step process that requires phosphorylation of p27 kip1 at threonine 187 by cyclin E/cdk, 18,19 recognition of T187-phosphorylated p27 kip1 by the ubiquitin ligase SCF Skp2, ubiquitylation, and degradation by the 26S proteasome of T187-phosphorylated p27 kip1. 12–14 Importantly, the loss of p27 kip1 expression and its presence in the cytoplasm of cancer cells are markers that predict shorter disease-free and/or overall survival in patients affected by different types of cancer. 4,6 Cytoplasmic sequestration of p27 kip1 is a mechanism whereby cancer cells overcome p27 kip1-imposed growth inhibition and has been reported for colon, 8 esophagus, 9 thyroid, 10 ovarian, 11 and breast carcinomas. 6,7 The level of p27 kip1 is reduced (or even absent) in ∼50% of human cancers. Two mechanisms govern p27 kip1 inactivation during human carcinogenesis: loss of protein expression and exclusion from the nuclear compartment. 4 However, because p27 kip1 inactivation is fundamental for the development of malignancies, p27 kip1 has been designated a tumor-suppressor protein. 3 Differently, the Cip/Kip Cdk inhibitor p27 kip1 does not fit the classic tumor-suppressor paradigm because mutations in the gene encoding p27 kip1 are rare. 2 Ink4 Cdk inhibitors are lost through deletion, point mutations, and/or promoter methylation in a variety of human neoplasms and are thus true tumor-suppressor genes. 1 Dysregulation of cell proliferation and failure to suppress tumor growth often result from alterations in the activity of Cdk inhibitors. Thus the PI3/AKT pathway and its effector p27 kip1 play major roles in thyroid carcinogenesis.ĭisruption of cell cycle control is frequent in human cancer. Analysis of 100 thyroid carcinomas indicated that p27 kip1 phosphorylation at T157/T198 and cytoplasmic mislocalization were preferentially associated with activation of the PI3K/AKT pathway. Finally, we evaluated whether these results were applicable to human tumors. Results obtained with phospho-specific antibodies and with transfection of nonphosphorylable p27 kip1 mutant constructs demonstrated that PI3K/AKT-dependent regulation of p27 kip1 mislocalization in thyroid cancer cells occurred via phosphorylation of p27 kip1 at T157 and T198 (but not at S10 or T187). Using specific PI3K inhibitors (LY294002, wortmannin, and PTEN) and a dominant active AKT construct (myrAKT), we demonstrated that the PI3K/AKT pathway controlled thyroid cell proliferation by regulating the expression and subcellular localization of p27.
Here we demonstrate that dysregulation of the PI3K/AKT pathway is important in thyroid carcinogenesis and that p27 kip1 is a key target of the growth-regulatory activity exerted by this pathway in thyroid cancer cells.
Functional inactivation of the tumor suppressor p27 kip1 in human cancer occurs either through loss of expression or through phosphorylation-dependent cytoplasmic sequestration.
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