Overexpression of MDM2 oncoprotein has been detected in a large number of diverse human malignancies and has been shown to play both p53-dependent and p53-independent roles in oncogenesis.
We found that CPHSP, a novel spirooxindole-pyrrolizidine derivative, can target the MDM2/p53 signaling that is essential for the tumorigenesis of hepatocellular carcinoma (HCC).
This investigation elucidated the mechanism of how MDM2 promotes genome instability and enhances tumorigenesis in the absence of p53, thus providing a theoretical and experimental basis for targeting MDM2 as a cancer therapy.
In vitro functional experiments revealed that the co-overexpression of MDM2 and CDK4 plays a key role in tumorigenesis by increasing cell growth and migration and inhibiting adipogenic differentiation potency when compared with the sole expression of MDM2 or CDK4.
Our results not only broaden the range of specific substrates of MDM2 beyond the cell cycle to include circadian components but also identify a previously unknown regulator of the clock as a druggable node that is often found to be deregulated during tumorigenesis.
These results reveal that YY1-CDKN3-MDM2/P53-P21 axis is involved in pancreatic tumorigenesis, which may develop new methods for human pancreatic cancer therapy.
Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood.
Proper function of the murine double minute 2 (MDM2)-p53 axis is known to prevent tumorigenesis and several metabolic diseases, yet its role in regulation of adipose tissue aging is still poorly understood.
This study showed that p16 and MDM2 polymorphisms do not play a decisive role in tumorigenesis, but some genotypes of these polymorphisms might be associated with follow-up characteristics of prolactinoma.
These data establish that the RP-MDM2-p53 pathway, in contrast to the p19ARF-MDM2-p53 pathway, is a critical mediator of colorectal tumorigenesis following APC loss.
In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.
It is well recognized that murine double minute gene 2 (MDM2) plays a critical role in cell proliferation and inflammatory processes during tumorigenesis.
These findings indicate that high-level MDM2 expression is needed in order to perform a critical p53-independent function and may obviate the need for genomic alterations to the p53 pathway during retinoblastoma tumorigenesis.
Indeed, a large body of work has shown that dysregulation of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation.