Oncogene
-
The E2f transcription factors are key downstream targets of the retinoblastoma protein tumor suppressor that control cell proliferation. E2F3 has garnered particular attention because it is amplified in various human tumors. E2f3 mutant mice typically die around birth and E2f3-deficient cells have a proliferation defect that correlates with impaired E2f target gene activation and also induction of p19(Arf) and p53. ⋯ This proliferation defect appears insufficient to disrupt normal development as E2f3a and E2f3b mutant mice are both fully viable and have no detectable defects. However, when combined with E2f1 mutation, inactivation of E2f3a, but not E2f3b, causes significant proliferation defects in vitro, neonatal lethality and also a striking cartilage defect. Thus, we conclude that E2f3a and E2f3b have largely overlapping functions in vivo and that E2f3a can fully substitute for E2f1 and E2f3 in most murine tissues.
-
Transforming growth factor (TGF)-beta is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-beta family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. ⋯ In addition, both TGF-beta3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-beta and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-beta promote invasion and bone metastasis of breast cancer.
-
The PTEN tumor suppressor was discovered by its homozygous deletion and other mutations in cancer. Since then, PTEN has been shown to be a non-redundant, evolutionarily conserved phosphatase whose function affects diverse cellular progresses such as cell cycle progression, cell proliferation, chemotaxis, apoptosis, aging, muscle contractility, DNA damage response, angiogenesis and cell polarity. In accordance with its ability to influence multiple crucial cellular processes, PTEN has a major role in the pathogenesis of numerous diseases such as diabetes, autism and almost every cancer examined. This review will discuss the diverse ways in which PTEN signaling is modified in cancer, and how these changes correlate with and might possibly affect the action of targeted chemotherapy.
-
Birt-Hogg-Dubé (BHD) syndrome is characterized by the development of pneumothorax, hair folliculomas and renal tumors and the responsible BHD gene is thought to be a tumor suppressor. The function of folliculin (Flcn), encoded by BHD, is totally unknown, although its interaction with Fnip1 has been reported. In this study, we identified a novel protein binding to Flcn, which is highly homologous to Fnip1, and which we named FnipL (recently reported in an independent study as Fnip2). ⋯ By the employment of siRNA, we observed a decrease in S6K1 phosphorylation in the BHD-suppressed cell. We also observed a decrease in S6K1 phosphorylation in FNIP1- and, to a lesser extent, in FNIPL/FNIP2-suppressed cells. These results suggest that Flcn-FnipL/Fnip2 and Flcn-Fnip1 complexes positively regulate S6K1 phosphorylation and that FnipL/Fnip2 provides an important clue to elucidating the function of Flcn and the pathogenesis of BHD.
-
The t(10;11)(p13;q14) translocation leads to the fusion of the CALM and AF10 genes. This translocation can be found as the sole cytogenetic abnormality in acute lymphoblastic leukemia, acute myeloid leukemia and in malignant lymphomas. The expression of CALM/AF10 in primary murine bone marrow cells results in the development of an aggressive leukemia in a murine bone marrow transplantation model. ⋯ Coexpression of CALM/AF10 but not of AF10 alters the subcellular localization of Ikaros in murine fibroblasts. The transcriptional repressor activity of Ikaros is reduced by AF10. These results suggest that CALM/AF10 might interfere with normal Ikaros function, and thereby block lymphoid differentiation in CALM/AF10 positive leukemias.