Fig. 2
From: Cellular senescence in cancer: clinical detection and prognostic implications
Molecular pathways of OIS and TIS. A Adequate senescence induction via participation of the DDR and the Ras-Raf-MEK-ERK, PI3K/AKT/mTOR and p38/MAPK signaling pathways resulting in functionally activated cell cycle inhibitor pathways (solid arrows) and upregulation of tumor suppressor proteins p53, p21WAF1/Cip1 and p16INK4a. Functional p21WAF1/Cip1 and/or p16INK4a induce a stable cell cycle arrest by inhibition of CDK (i.e., CDK1, CDK2, CDK4 and CDK6)—cyclin (i.e., cyclin A, E and D) complexes, thereby preventing phosphorylation of the retinoblastoma protein (solid inhibitor lines), which blocks S-phase entry and induces senescence (solid arrow). B Inadequate senescence induction or escape from senescence due to (acquired) mutations, deletions, secondary alterations and/or promoter silencing affecting cellular control genes TP53 (encoding p53), CDKN1A (encoding p21WAF1/Cip1) CDKN2A (encoding p16INK4a), resulting in absent or dysfunctional cell cycle inhibitor pathway activation (dotted arrow) and absent or dysfunctional tumor suppressor proteins to induce or maintain senescence (dotted inhibitor lines and arrow). Depending on whether the DNA damage is repaired, the cell may resume proliferation or go into apoptosis. * p21WAF1/Cip1 can also be activated by pathways that are independent of p53 [125]. OIS, oncogene-induced senescence; TIS, therapy-induced senescence; DDR, DNA damage response; CDK, cyclin-dependent kinase; pRb, retinoblastoma protein