To survive inhospitable environments, tumor cells are forced to remodel their signaling pathways by altering transcription, translation, and post-translational modifications. This adaptation is ...regulated in a spatial and temporal manner and gives rise to individual tumor cells with distinct gene expression and metabolic signatures. Such phenotypic heterogeneity is the result of tumor cell plasticity, which-together with the genetic background of the tumor-determines whether cells resist environmental stress, enter dormancy, or metastasize. This review summarizes our understanding of how tumor cells exploit the cellular stress response to balance proliferation, differentiation, and survival signals, and to remodel local and distant environments. We focus in particular on tumor metastasis, which is the greatest impediment to clinical management of cancers today.
Summary
In tumor cells, the ability to maintain viability over long time periods without proliferation is referred to as a state of dormancy. Maintenance of dormancy is controlled by numerous ...cellular and environmental factors, from immune surveillance and tumor–stroma interaction to intracellular signaling. Interference of dormancy (to an ‘awaken’ state) is associated with reduced response to therapy, resulting in relapse or in metastatic burst. Thus, maintaining a dormant state should prolong therapeutic responses and delay metastasis. Technical obstacles in studying tumor dormancy have limited our understanding of underlying mechanisms and hampered our ability to target dormant cells. In this review, we summarize the progress of research in the field of immunogenic, angiogenic, and cellular dormancy in diverse malignancies with particular attention to our current understanding in melanoma.
MEKK1/JNK Signaling Stabilizes and Activates p53 Fuchs, Serge Y.; Adler, Victor; Pincus, Matthew R. ...
Proceedings of the National Academy of Sciences - PNAS,
09/1998, Letnik:
95, Številka:
18
Journal Article
Recenzirano
Odprti dostop
Activation of the tumor suppressor p53 by stress and damage stimuli often correlates with induction of stress kinases, Jun-NH2kinase (JNK). As JNK association with p53 plays an important role in p53 ...stability, in the present study we have elucidated the relationship between the JNK-signaling pathway and p53 stability and activity. Expression of a constitutively active form of JNKK upstream kinase, mitogen-activated protein kinase kinase kinase (Δ MEKK1), increased the level of the exogenously transfected form of p53 in p53 null (10.1) cells as well as of endogenous p53 in MCF7 breast cancer cells. Increased p53 level by forced expression of Δ MEKK1 coincided with a decrease in p53 ubiquitination in vivo and with prolonged p53 half-life. Computerized modeling of the JNK-binding site (amino acids 97-116; p7 region) enabled us to design mutations of exposed residues within this region. Respective mutations (p53101-5-8) and (p53Δ p7) forms of p53 did not exhibit the same increase in p53 levels upon Δ MEKK1 expression. In vitro phosphorylation of p53 by JNK abolished Mdm2 binding and targeting of p53 ubiquitination. Similarly, Δ MEKK1 expression increased p53 phosphorylation by immunopurified JNK and dissociated p53-Mdm2 complexes. Transcriptional activity of p53, as measured via mdm2 promoter-driven luciferase, exhibited a substantial increase in Δ MEKK1-expressing cells. Cotransfection of p53 and Δ MEKK1 into p53 null cells potentiated p53-dependent apoptosis, suggesting that MEKK1 effectors contribute to the ability of p53 to mediate programmed cell death. Our results point to the role of MEKK1-JNK signaling in p53 stability, transcriptional activities, and apoptotic capacity as part of the cellular response to stress.
RING-finger ubiquitin ligases elicit ubiquitination of their substrates, which is balanced by their self-ubiquitination. New insights into regulating the switch between these two modes are ...illustrated by the role of the adaptor protein Daxx (death domain-associated protein) in regulating the deubiquitinating enzyme HAUSP which, in turn, directs the ligase activity of Mdm2.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
5.
Melanoma biology and progression Herlyn, M; Ferrone, S; Ronai, Z ...
Cancer research,
2001-Jun-01, 20010601, Letnik:
61, Številka:
11
Journal Article, Conference Proceeding
Ubiquitin chains in the ladder of MAPK signaling Laine, Aaron; Ronai, Ze'ev
Science's signal transduction knowledge environment (STKE),
2005-Apr-26, Letnik:
2005, Številka:
281
Journal Article
With a better understanding of the cellular stress response, it has become evident that catalytic modules consisting of kinases that mediate the activation of downstream effector components are ...subject to multiple layers of regulation. Such regulatory mechanisms are not limited to those involving scaffold proteins or protein phosphatases, and they appear to include a growing number of modifications by ubiquitin and ubiquitin-like proteins. The role of ubiquitin in the regulation of mitogen-activated protein kinase (MAPK) emerges as a paradigm for understanding the role of ubiquitination in regulating other signal transduction pathways. Ubiquitination influences signal diversification and limits the duration of the signal through its role in the assembly of protein kinase complexes, subcellular localization, and the actual degradation of the kinase or its substrate. This review summarizes our current understanding of the roles of ubiquitin in regulating MAPK signaling.
RAS gene-encoded p21 protein has been found to increase in vitro phosphorylation of JUN via its kinase, JUN N-terminal kinase (JNK). This effect is mediated by increased phosphorylation of JNK in the ...presence of wild-type and oncogenic (Val-12) p21 protein in a dose-dependent manner. Oncogenic p21 protein is more potent in mediating this effect than its normal counterpart. Both normal and oncogenic p21 proteins bind to purified JNK and to JNK that is present in cell extracts from transformed fibroblasts and melanoma cells. Oncogenic and normal p21 proteins have also been found to bind to bacterially expressed JUN protein. This binding is dose dependent, enhanced by the presence of GTP, and depends on the presence of the first 89 amino acids of JUN (the delta domain), as it does not occur with v-jun. While the ability of both normal and oncogenic p21 proteins to bind JNK is strongly inhibited by a p21 peptide corresponding to aa 96-110, and more weakly inhibited by the p21 peptide corresponding to aa 115-126, p21-JUN interaction is inhibited by peptides corresponding to aa 96-110 and, to a lesser degree, by peptides corresponding to aa 35-47. The results suggest that the p21 protein interacts specifically with both JNK and JUN proteins.
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