Research Paper Volume 16, Issue 13 pp 10749—10764

Figure 7. Proposed diagram showing a signaling pathway that leads to the activation of p16-dependent cellular senescence in response to telomeric shortening, DNA damage, and oxidative stress. Based on our findings, we believe that telomeric shortening, DNA damage, and oxidative stress can transcriptionally activate CTSL, which results in the transcriptional activation of CUX1. As a result, p16^INK4a is activated by CUX1 via its binding to the atherosclerosis-associated fSNP rs1537371, inducing cellular senescence. As CTSL is not a transcription factor and CTSL protease activity is required for the activation of CUX1 as well as cellular senescence, we believe that in between CTSL and CUX1, there is a currently unknown transcription factor X that can be proteolytically activated by CTSL and transcribe CUX1.