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_4 label "Selventa" provenance.
_3 value "While the studies with RB and E2F families have greatly advanced our understanding of G1 progression, the increasingly complex picture for RB regulation underscores the need for a \"whole signaling pathway\" viewpoint. The summary of various crosses of RB and E2F family deletions and other complementary experiments (Macleod, 1999; Classon et al., 2000a and Classon et al., 2000b) clearly show that E2F cannot participate in all the phenotypes that are attributed to RB. A review by Dyson and colleagues has tabulated many other RB interacting proteins that are considerably less characterized than the E2Fs (reviewed in Morris and Dyson, 2001). Certainly, much knowledge has been gained from the E2F studies, but the investigation of non-E2F and RB interacting proteins will be necessary to account for all RB-dependent tumor suppressor and differentiation functions. The take-home lesson is that the functions of tumor suppressor genes and oncogenes must be investigated in the context of a complete signaling network. While genetic mutations are clearly important, subtle biochemical regulation without genetic mutation may have significant consequences for cancer. The discovery of biochemical dysregulation requires an in-depth knowledge and appreciation of complex signaling networks. 1.1.1. Objective Our work in this area initially began as an effort to identify non-E2F targets of RB and p130 for cell cycle arrest. The objective was to identify proteins that enforce a proliferation barrier in differentiated tissues. We identified the HMG-box containing protein (HBP1) transcriptional repressor initially as an RB target (Tevosian et al., 1997). The first section will summarize current knowledge on the HBP1 transcription factor and its gene targets in the context of cell cycle control and tumor suppression. Our objective is to review evidence for a new network for cell cycle regulation involving both the p38 MAP kinase pathway, and HBP1 and to their possible involvement in a new tumor suppressive signaling network. In this review, the work of several investigators to define other HBP1 target genes for proliferation and for tumor suppression is summarized. In addition, we summarize our recent studies that have implicated HBP1 in the control of intracellular reactive oxygen species generation, which has been implicated in mitogenic signaling. Together, these studies make a case for HBP1 in regulating diverse aspects of cell proliferation. The second section will summarize recent studies on the p38 MAP kinase signaling pathways in cell cycle control and senescence and propose possible connections to the published HBP1 studies. The final section will describe ongoing and future directions that would advance this new signaling network for tumor suppression with a view towards cancer diagnosis and treatment. 2. The HBP1 transcription factor: pathways and gene targets Initially, HBP1 was cloned in a screen for cDNAs that complemented a potassium channel defect, although HBP1 was clearly noted as a transcription factor (Lesage et al., 1994). Interestingly, there are reports of potassium channels that are linked to differentiation and to cancer (e.g., Mu et al., 2003), so the possibility that HBP1 may control ion channel gene expression in cancer may be an intriguing question. As described below, we and other groups re-isolated HBP1 as an RB and p130 interacting protein (Lavender et al., 1997 and Tevosian et al., 1997). Our labs have investigated HBP1 and its transcriptional functions in the context of tumor suppressive and oncogenic pathways (see below). 2.1. HBP1, G1 control and cancer Our goal was discovering regulators of differentiation that trigger irreversible cell cycle exit. To this day, the RB family members RB and p130 are the best-defined regulators of quiescence and differentiation within the RB family (Classon et al., 2000a; Classon et al., 2000b and Classon and Dyson, 2001). The rol..." provenance.
_3 wasQuotedFrom 15225871 provenance.
assertion hadPrimarySource 15225871 provenance.
large_corpus.bel title "BEL Framework Large Corpus Document" provenance.
large_corpus.bel description "Approximately 61,000 statements." provenance.
assertion wasDerivedFrom _3 provenance.
assertion wasDerivedFrom large_corpus.bel provenance.
large_corpus.bel authoredBy _4 provenance.
large_corpus.bel version "20131211" provenance.