The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

Abstract

Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16INK4A , a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies

“…Data from in vivo experiments involving different mouse cancer models and human epithelial samples demonstrated that ARF activation occurs later than the DDR one and it is also rare. The delayed induction of ARF has been suggested to be due to the requirement of a higher threshold of oncogenic load compared to DDR [56]. Results from another study outlined the relationship between ARF and ATM, as it was shown that there is an up-regulation of ARF in the case of inhibition of ATM or loss of its expression, thus supporting the importance of ARF's role as a complementary anticancer barrier against tumor progression [57].…”

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

“…These include common roles in the protection of the reproductive system [150-152], in development [153-159], aging [160, 161], cell death [162-164], cancer [159, 165-167], redox regulation [161, 168, 169], and metabolism [168, 170, 171]. Moreover, as is the case for p53 [172, 173], p63 is an important factor in cancer response to therapy as p63 and p53 are found in similar molecular complexes that mediate cisplatin resistance [174].…”

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

“…15 Much of the research in the quest for E3 inhibitors has been finalized for the p53-HDM2 pathway since p53 is an extremely powerful transcription factor crucial in DNA damage response. [16][17][18][19][20][21] Here, the cellular defense to DNA damage is based on sensors and effectors that activates the cell death pathway, [22][23][24] via p53 [25][26][27][28][29] or its family members. [30][31][32][33][34][35][36][37] Like for our recent Itch inhibitor screening, 14 we believe that in a near future innovative E3 inhibitors will be developed.…”