In multiple tumor types, activation of the transcription factor NF-B increases the resistance of tumor cells to anticancer therapies and contributes to tumor progression. Genotoxic stress induced by chemotherapy or radiation therapy triggers the ATM-dependent translocation of NF-B essential modifier (NEMO), also designated I B kinase ␥ (IKK␥), from the nucleus to the cytosol, resulting in I B kinase activation by mechanisms not yet fully understood. RIP1 has been implicated in this response and found to be modified in cells with damaged DNA; however, the nature of the RIP1 modification and its precise role in the pathway remain unclear. Here, we show that DNA damage stimulates the formation of a cytosolic complex containing ATM, NEMO (IKK␥), RIP1, and TAK1. We find that RIP1 is modified by SUMO-1 and ubiquitin in response to DNA damage and demonstrate that modified RIP1 is required for NF-B activation and tumor cell survival. We show that ATM activates TAK1 in a manner dependent on RIP1 and NEMO. We also reveal TAK1 as a central mediator of the alternative DNA damage response pathway mediated by the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 (MAPKAP-2) kinases. These findings have translational implications and reveal RIP1 and TAK1 as potential therapeutic targets in chemoresistance.The DNA damage response activates cell cycle checkpoint and survival pathways that function to prevent DNA replication until damaged DNA is repaired. These pathways include the well-characterized ATM (ataxia telangiectasia mutated)/ CHK2 and ATR (ataxia telangiectasia and Rad-3 related)/ CHK1 pathways and the more recently identified ATM/ ATR/p38 mitogen-activated protein kinase (MAPK)/MAPKactivated protein 2 (MAPKAP-2; hereinafter called MK2) checkpoint that is active in p53-deficient tumor cells (15,19). The transcription factor NF-B regulates apoptosis induced by genotoxic stress and is an attractive therapeutic target in tumor cells whose response to DNA-damaging agents is impaired due to compromised p53 function. Moreover, constitutive NF-B activity is a hallmark of several cancers, and mutations in NF-B pathway components have been associated with the activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), breast cancer, and multiple myeloma (3, 6). Thus, the inclusion of NF-B inhibitors in cancer therapy could have antioncogenic activities as well as augment the tumor chemotherapeutic response.NF-B is normally held in the cytoplasm in an inactive form bound to inhibitor proteins, such as I B␣. Diverse stimuli, such as infection, proinflammatory cytokine production, or treatment with agents that induce DNA damage elicit NF-B-mediated transcriptional activity by activating the cytosolic I B kinase (IKK) complex, consisting of IKK␣ and IKK and a regulatory subunit designated IKK␥ or NF-B essential modifier (NEMO) (hereinafter referred to as NEMO). IKK activation results in I B␣ phosphorylation, ubiquitination, and subsequent degradation. The NF-B (p65/p50) heterodimer is then free to en...
High-risk human papillomaviruses, such as HPV16, cause cervical cancers, other anogenital cancers, and a subset of head and neck cancers. E6 and E7, two viral oncogenes expressed in these cancers, encode multifunctional proteins best known for their ability to bind and inactivate the tumor suppressors p53 and pRb, respectively. In skin carcinogenesis experiments using E6 transgenic (K14E6 WT ) mice, HPV16 E6 was found to contribute to two distinct stages in skin carcinogenesis: promotion, a step involved in the formation of benign papillomas, and progression, the step involved in the malignant conversion of benign tumors to frank cancer. In this study, we compared the tumorigenic properties of K14E6 WT mice with those of K14E6 D146-151 mice, which express a mutant form of E6 that cannot bind a family of cellular proteins known as PDZ domain proteins but retains the ability to inactivate p53. In skin carcinogenesis experiments, the K14E6 D146-151 transgene failed to contribute to the promotion stage of skin carcinogenesis but retained the ability to contribute to the progression stage. Cytogenetic analysis indicated that, although gains of chromosome 6 are consistently seen in tumors arising on K14E6 WT mice, they are infrequently seen in tumors arising on K14E6 D146-151 mice. This observation supports the premise that the nature of cancer development in these two mouse strains is distinct. Based on these studies, we conclude that E6 contributes to cancer through its disruption of multiple cellular pathways, one of which is mediated through its interaction with PDZ domain partners and the other through E6's inactivation of p53. (Cancer Res 2005; 65(18): 8266-73)
The development of specialized organs is tightly linked to the regulation of cell growth, orientation, migration and adhesion during embryogenesis. In addition, the directed movements of cells and their orientation within the plane of a tissue, termed planar cell polarity (PCP), appear to be crucial for the proper formation of the body plan. In Drosophila embryogenesis, Discs large (dlg) plays a critical role in apical-basal cell polarity, cell adhesion and cell proliferation. Craniofacial defects in mice carrying an insertional mutation in Dlgh-1 suggest that Dlgh-1 is required for vertebrate development. To determine what roles Dlgh-1 plays in vertebrate development, we generated mice carrying a null mutation in Dlgh-1. We found that deletion of Dlgh-1 caused open eyelids, open neural tube, and misorientation of cochlear hair cell stereociliary bundles, indicative of defects in planar cell polarity (PCP). Deletion of Dlgh-1 also caused skeletal defects throughout the embryo. These findings identify novel roles for Dlgh-1 in vertebrates that differ from its well-characterized roles in invertebrates and suggest that the Dlgh-1 null mouse may be a useful animal model to study certain human congenital birth defects.
The deubiquitinating enzyme CYLD is a tumor suppressor protein known for its role in repression of generally pro-oncogenic NF-kappaB activation pathways. Two new studies published in this and the September issue of Developmental Cell show that CYLD dismantles distinct types of polyubiquitin chains formed on select signaling proteins and is thereby required for normal vertebrate and invertebrate development.
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