Senescence stimuli activate multiple tumor suppressor pathways to initiate cycle arrest and a differentiation program characteristic of senescent cells. We performed a two-stage, gain-of function screen to select for the genes whose enhanced expression can bypass replicative senescence. We uncovered multiple genes known to be involved in p53 and Rb regulation, ATM regulation and two components of the CST complex involved in preventing telomere erosion and additional genes such as REST and FOXO4 that have been implicated in aging. Among the new genes now implicated in senescence we identified DLX2, a Homeobox transcription factor that has been shown to be required for tumor growth, metastasis and associates with poor cancer prognosis. Growth analysis showed that DLX2 expression led to increased cellular replicative lifespan. We found that DLX2 expression inhibited p53 activation, and DLX2 reduced the protein level of upstream activator kinases ATM and DNA-PK. Our data suggest that DLX2 expression reduces the protein components of the TTI1/TTI2/TEL2 complex, a key complex required for the proper folding and stabilization of ATM, DNA-PK and other members of the PIKK family. Over-expression of DLX2 exhibit mutual exclusivity with p53 alteration in cancer patients, suggesting DLX2 may attenuate the p53 pathway during tumor formation. Our functional screen identified novel players that may promote tumorigenesis by regulating the ATM-p53 pathway and senescence. / Medical Sciences
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/26718730 |
| Date | 01 September 2016 |
| Creators | Wang, Yifan |
| Contributors | Harper, Wade |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation, text |
| Format | application/pdf |
| Rights | open |
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