scholarly journals Tumor Suppressor Activity of Profilin Requires a Functional Actin Binding Site

2004 ◽  
Vol 15 (4) ◽  
pp. 1600-1608 ◽  
Author(s):  
Nina Wittenmayer ◽  
Burkhard Jandrig ◽  
Martin Rothkegel ◽  
Kathrin Schlüter ◽  
Wolfgang Arnold ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Ligand Binding ◽  
Binding Site ◽  
Nude Mice ◽  
Human Cancer ◽  
Cancer Cell Line ◽  
Actin Binding ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Actin Binding Site

Profilin 1 (PFN1) is a regulator of the microfilament system and is involved in various signaling pathways. It interacts with many cytoplasmic and nuclear ligands. The importance of PFN1 for human tissue differentiation has been demonstrated by the findings that human cancer cells, expressing conspicuously low PFN1 levels, adopt a nontumorigenic phenotype upon raising their PFN1 level. In the present study, we characterize the ligand binding site crucial for profilin's tumor suppressor activity. Starting with CAL51, a human breast cancer cell line highly tumorigenic in nude mice, we established stable clones that express PFN1 mutants differentially defective in ligand binding. Clones expressing PFN1 mutants with reduced binding to either poly-proline-stretch ligands or phosphatidyl-inositol-4,5-bisphosphate, but with a functional actin binding site, were normal in growth, adhesion, and anchorage dependence, with only a weak tendency to elicit tumors in nude mice, similar to controls expressing wild-type PFN1. In contrast, clones expressing a mutant with severely reduced capacity to bind actin still behaved like the parental CAL51 and were highly tumorigenic. We conclude that the actin binding site on profilin is instrumental for normal differentiation of human epithelia and the tumor suppressor function of PFN1.

scholarly journals Analysis of RAS as a tumor suppressor

2017 ◽  
Author(s):  
Chelsey Kenney ◽  
Edward C. Stites
Keyword(s):  
Tumor Suppressor ◽  
Protein Expression ◽  
Gene Dosage ◽  
Human Cancer ◽  
Alternative Hypothesis ◽  
Suppressor Activity ◽  
Ras Protein ◽  
Ras Gtpases ◽  
Suppressor Effect ◽  
Tumor Suppressor Activity

ABSTRACTThe RAS GTPases are among the best-understood oncogenes that promote human cancer. Many have argued that non-mutated, wild-type, RAS also functions as a tumor suppressor. The arguments for RAS tumor suppressor activity often involve data that are claimed to be inconsistent with known principles of RAS biology. RAS tumor suppressor activity is invoked to explain these observations. Here, we consider an alternative hypothesis: these data are actually consistent with RAS biology. We investigate by using our previously developed mathematical model of RAS regulation. We find that three of five arguments for RAS having tumor suppressor activity are based upon data that the model demonstrates are actually consistent with known RAS biology. We also find that the other two types of data interpreted to indicate a tumor suppressor effect can be explained by our model with the additional assumption that RAS protein expression does not vary proportionally with gene dosage. Measurements of RAS protein expression as a function of gene dosage could help resolve whether or not RAS has tumor suppressor activity. Overall, we conclude that the evidence for RAS having tumor suppressor activity is much less strong that it has appeared.

Targeting the p53 tumor suppressor activity in glioblastomas using small molecule MDM2-inhibitor

2011 ◽  
Vol 42 (01) ◽  
Author(s):  
P. Monfared ◽  
T. Viel ◽  
G. Schneider ◽  
Y. Waerzeggers ◽  
S. Rapic ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Small Molecule ◽  
Suppressor Activity ◽  
P53 Tumor Suppressor ◽  
Tumor Suppressor Activity ◽  
Mdm2 Inhibitor

scholarly journals Evidence that a 27-residue sequence is the actin-binding site of ABP-120

1991 ◽  
Vol 266 (20) ◽  
pp. 12989-12993
Author(s):  
A.R. Bresnick ◽  
P.A. Janmey ◽  
J. Condeelis
Keyword(s):  
Binding Site ◽  
Actin Binding ◽  
Actin Binding Site

Merlin cooperates with neurofibromin and Spred1 to suppress the Ras–Erk pathway

2020 ◽  
Author(s):  
Yan Cui ◽  
Lin Ma ◽  
Stephan Schacke ◽  
Jiani C Yin ◽  
Yi-Ping Hsueh ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Binding Sites ◽  
Neurofibromatosis Type ◽  
Kinase Domain ◽  
Erk Pathway ◽  
Suppressor Activity ◽  
The Third ◽  
Tumor Suppressor Activity ◽  
Multiple Signaling

Abstract The Ras–Erk pathway is frequently over-activated in human tumors. Neurofibromatosis type 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that merlin interacts with Ras and p120RasGAP. Here, we show that merlin can also interact with the neurofibromin/Spred1 complex via merlin-binding sites present on both proteins. Further, merlin can directly bind to the Ras-binding domain and the kinase domain of Raf1. As the third component of the neurofibromin/Spred1 complex, merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a ‘selective Ras barrier’. Merlin-deficient Schwann cells require the Ras–Erk pathway activity for proliferation. Accordingly, suppression of the Ras–Erk pathway likely contributes to merlin’s tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.

scholarly journals Autophagy augments the self-renewal of lung cancer stem cells by the degradation of ubiquitinated p53

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jianyu Wang ◽  
Doudou Liu ◽  
Zhiwei Sun ◽  
Ting Ye ◽  
Jingyuan Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Lines ◽  
Human Cancer ◽  
Suppressor Activity ◽  
Self Renewal ◽  
Tumor Suppressor Activity ◽  
Lung Cancer Stem Cells ◽  
First Time

AbstractIt has been postulated that cancer stem cells (CSCs) are involved in all aspects of human cancer, although the mechanisms governing the regulation of CSC self-renewal in the cancer state remain poorly defined. In the literature, both the pro- and anti-oncogenic activities of autophagy have been demonstrated and are context-dependent. Mounting evidence has shown augmentation of CSC stemness by autophagy, yet mechanistic characterization and understanding are lacking. In the present study, by generating stable human lung CSC cell lines with the wild-type TP53 (A549), as well as cell lines in which TP53 was deleted (H1229), we show, for the first time, that autophagy augments the stemness of lung CSCs by degrading ubiquitinated p53. Furthermore, Zeb1 is required for TP53 regulation of CSC self-renewal. Moreover, TCGA data mining and analysis show that Atg5 and Zeb1 are poor prognostic markers of lung cancer. In summary, this study has elucidated a new CSC-based mechanism underlying the oncogenic activity of autophagy and the tumor suppressor activity of p53 in cancer, i.e., CSCs can exploit the autophagy-p53-Zeb1 axis for self-renewal, oncogenesis, and progression.

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