S W Lowe

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..An intense research effort is uncovering the underlying mechanisms of apoptosis such that, in the next decade, one envisions that this information will produce new strategies to exploit apoptosis for therapeutic benefit...

..Recent evidence emerging from mouse tumor models distinguishes the activities of p16(Ink4a) and p19(Arf) in regulating tumor onset and identifies differences in their responsiveness to drugs...

..Consequently, constitutive MAPK signaling activates p53 and p16 as tumor suppressors...

..Understanding extracellular cues that regulate these processes may enable new therapies for these conditions...

..Consequently, INK4a/ARF and p53 mutations lead to aggressive tumors by disrupting overlapping tumor suppressor functions. These data have important implications for understanding the clinical behavior of human tumors...

..This model, able to test any other candidate gene, will be particularly useful to study the implications of specific mutations for drug action in vivo...

..Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type...

..This model provides a powerful platform for applications like cancer gene discovery or high-throughput preclinical drug testing...

..Synergistic effects between the p19(ARF) and DNA damage pathways in inducing p53 may contribute to E1A's ability to enhance radio- and chemosensitivity...

..As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells...

..Thus, oncogenic ras can activate the ARF-p53 program to suppress epithelial cell transformation. Disruption of this program may be important during skin carcinogenesis and the development of other carcinomas...

..Negation of ras-induced senescence may be relevant during multistep tumorigenesis...

..These results highlight the utility of pooled shRNA screens for identifying genetic determinants of chemotherapy response and suggest strategies for improving the effectiveness of topoisomerase poisons in the clinic...

..Understanding these genotype-response relationships in human tumors will be important for the effective use of rapamycin or other compounds targeting the PI(3)K pathway in the clinic...

..Thus, because the RB pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer...

..These results demonstrate that transient Mad2 overexpression and chromosome instability can be an important stimulus in the initiation and progression of different cancer subtypes...

..Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy...

..These data identify CBX7 as a chromobox protein causally linked to cancer development and may help explain the low frequency of INK4a/ARF mutations observed in human follicular lymphoma...

..Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer...

..Our results indicate that the extent by which rapamycin can modulate expression of Mcl-1 is an important feature of the rapamycin response...

..These data reinforce the growing awareness that non-coding RNAs are key players in tumour development by placing miRNAs in a central role in a well-known tumour-suppressor network...

..These results establish that targeting translation initiation can restore drug sensitivity in vivo and provide an approach to modulating chemosensitivity...

..In practice, this primary microRNA-based short hairpin RNA vector system is markedly similar to cDNA overexpression systems and is a powerful tool for studying gene function in cells and animals...

..These results identify p400 as a regulator of the ARF-p53 pathway and a component of the cellular machinery that couples proliferation to cell death...

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..Therefore, apoptosis is the only p53 function selected against during lymphoma development, whereas defective cell-cycle checkpoints and aneuploidy are mere byproducts of p53 loss...

..The data also underscore how cell cycle progression can be coupled to the apoptotic machinery...

..In addition, intrinsic differences between individual shRNA expression vectors targeting the same gene can be used to create an 'epi-allelic series' for dissecting gene function in vivo...

..These results provide a molecular explanation for the stability of the senescent state, as well as new insights into the action of Rb as a tumor suppressor...

..Understanding this network in more detail will provide insights into cancer and other diseases, and will identify strategies to improve their therapeutic treatment...

..Here we show how these changes might contribute to the stability of the senescent state...

..They also illustrate the importance of tailoring cancer therapy based on tumor genotype...

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..Although oncogenic mutations that disable such networks can have profound and varied effects on tumour evolution, they may leave intact latent tumour-suppressive potential that can be harnessed therapeutically...

..These findings reveal a role for MbIII in Myc biology, and establish that the oncogenic capacity of Myc is linked directly to its ability to temper the apoptotic response...