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Regulation of mitosis through mitotic checkpoints is critical to prevent propagation of DNA damage and to ensure proper DNA content of the resulting daughter cells. Loss of these checkpoint functions may lead to neoplasias or cancers. The protein checkpoint with forkhead associated and RING domains (CHFR) has been implicated as a tumor suppressor in a multitude of cancers. Originally identified as a major component of the antephase checkpoint, CHFR has recently been associated with the spindle assembly checkpoint through its interaction with MAD2. To further understand the role of CHFR in this checkpoint, we deleted key functional domains from the CHFR protein and investigated the effects on MAD2 binding and function. We found that the C-terminal cysteine-rich domain of CHFR is required for the CHFR/MAD2 interaction. In addition,...
Head and neck cancer (HNSCC) is the sixth most common cancer in the world but its treatment has not significantly improved in several decades. Pro-inflammatory mediators such as interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), prostaglandin 2 (PGE2) and matrix metalloproteinases (MMPs) promote tumor invasion and angiogenesis. However, targeted inhibition of individual pro-inflammatory mediators or their receptors had limited success in the treatment of HNSCC. This is likely due to redundancy in function between pro-inflammatory mediators. Therefore, an attractive treatment target would be a common mechanism that regulates multiple pro-inflammatory mediators in HNSCC. The objective of this dissertation is to identify molecular mechanisms such as Tristetraprolin (TTP), an RNA-binding protein that mediates the decay of mul...
Cell division is a highly regulated process. Checkpoints can halt cell-cycle progression due to adverse conditions such as misalignment of chromosomes to prevent missegregation. The search for new regulators of the cell cycle revealed the mitotic checkpoint gene CHFR (checkpoint with forkhead-associated and ring finger). CHFR coordinates an early mitotic phase by delaying chromosome condensation in response to a mitotic stress. Because aneuploidy and chromosome instability are common in malignant breast tumors, we screened 24 breast cancer cell lines for CHFR expression and demonstrated that 50% (12 of 24) of breast cancer cell lines had low CHFR levels. Expression of CHFR was reactivated with the demethylating agent 5-aza-2′-deoxycytidine (5-aza-dC) in two low- CHFR –expressing cell lines. Eleven of these 12 (92%) low- CHFR ...
Noonan syndrome is a multiple congenital anomaly condition characterized by craniofacial anomalies, short stature, cardiac malformations, and normal peripheral blood karyotype analysis. Prior reports of individuals with Noonan syndrome have revealed an association with several autoimmune diseases, including vasculitis and anterior uveitis, but no reports of systemic lupus erythematosus (SLE). Here we present the first case report of a 21-year-old man with a clinical diagnosis of Noonan syndrome and a recent history of mitral valve dysfunction and systemic lupus erythematosus. We discuss his findings in the context of known features of Noonan syndrome and propose that individuals with Noonan syndrome be regularly monitored for associated autoimmune phenomena. © 2001 Wiley-Liss, Inc.
The Neurofibromatosis Type 1 (NF1) gene functions as a tumor suppressor gene. Loss of its protein, neurofibromin, in the autosomal dominant disorder NF1 is associated with peripheral nervous system tumors, particularly neurofibromas, benign lesions in which the major cell type is the Schwann Cell (SC). Benign and malignant human tumors found in NF1 patients are heterogeneous with respect to their cellular composition. The number and size of neurofibromas in NF1 patients has been shown to increase during pregnancy, with, in some cases, post-partum regression, which suggests hormonal involvement in this increase. However, in this review, we consider evidence from the literature that both direct hormonal influence on tumor growth and on angiogenesis may contribute to these effects. © 2008 Wiley-Liss, Inc.
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