Abstract
p21cip1/waf1 mediates various biological activities by sensing and responding to multiple stimuli, via p53-dependent and independent pathways. p21 is known to act as a tumor suppressor mainly by inhibiting cell cycle progression and allowing DNA repair. Significant advances have been made in elucidating the potential role of p21 in promoting tumorigenesis. Here, we discuss the involvement of p21 in multiple signaling pathways, its dual role in cancer, and the importance of understanding its paradoxical functions for effectively designing therapeutic strategies that could selectively inhibit its oncogenic activities, override resistance to therapy and yet preserve its tumor suppressive functions.
Highlights
Cell cycle checkpoint mechanisms are crucial for the protection and maintenance of genome integrity during exposure to multiple stress signals
One important regulator of cell cycle progression is the cyclin-dependent kinase inhibitor p21cip1/waf1, which is transactivated by p53 and is known to exert dual role during tumorigenesis [4]
Cell cycle progression is tightly controlled by cyclins and cyclin-dependent kinases (CDKs), the sequential activation of which allows for the initiation of and transition between different phases of the cell cycle
Summary
Cell cycle checkpoint mechanisms are crucial for the protection and maintenance of genome integrity during exposure to multiple stress signals. The activated cyclin/CDK complexes phosphorylate and inactivate members of the retinoblastoma (Rb) protein family, including pRb, promoting progression through. Several other transcription factors induce p21 and include signal transducers and activators of transcription (STAT), E2F-1/E2F-3, Smads, AP2, BETA2, GAX, CCAAT/enhancer binding protein-α (C/EBPα), C/EBPβ, and myoblast determination protein 1 (MYOD1). Pin has been shown to regulate p53 stability and the transcriptional activation of p21 in response to DNA damage [31] This occurs by inducing conformational changes in p53 and thereby facilitating its phosphorylation at Ser-33 and -46 [32]. A member of the Krüppel-like transcription factor (Klf) family that regulate cellular proliferation, KLF4, mediates damage-induced p53 response by upregulating p21 expression and inducing cell cycle arrest at G1 phase [36].
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