The Regulation of Cellular Functions by the p53 Protein: Cellular Senescence

Abstract

Transformed cells have properties that allow them to survive and proliferate inappropriately. These characteristics often arise as a result of mutations caused by DNA damage. p53 suppresses transformation by removing the proliferative or survival capacity of cells with DNA damage or inappropriate cell-cycle progression. Cellular senescence, marked by morphological and gene expression changes, is a critical component of p53-mediated tumor suppression. In response to stress, p53 can facilitate an arrest and senescence program in cells exposed to stresses such as DNA damage and oncogene activation, preventing transformation. Senescent cells are evident in precancerous adenoma-type lesions, whereas proliferating, malignant tumors have bypassed senescence, either by p53 mutation or inactivation of the p53 pathway by other means. Tumors that have retained wild-type p53 often show a p53-mediated senescence response to chemotherapy. This response is actually detrimental in some tumor types, as senescent cells can drive relapse by persisting and producing cytokines and chemokines through an acquired secretory phenotype.

ZNF667 Serves as a Putative Oncogene in Human Hepatocellular Carcinoma

“…Functioning as a tumor suppressor by removing the proliferative or survival capacity of cells with DNA damage or inappropriate cell-cycle progression, p53 has been described as "the guardian of the genome" [37, 38]. The experiments also proved that over expression of ZNF667 could inhibit the increase of p53 in Dox-induced H9c2 cells (unpublished data).…”

p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

“…The most well-known tumor suppressor function of p53 is based on its ability to promote transient cell cycle arrest, apoptosis, and a permanent form of growth arrest known as senescence [13]. The p53 protein mediates these responses by transcriptionally activating target genes such as p21, which is involved in both permanent and transient cell cycle arrest [14][15][16][17], and proapoptotic BCL2 family members such as Noxa and BBC3/PUMA (BCL2 binding component 3) [18,19], which mediate apoptosis ( Figure 1). In particular, p53 mediated activation of p21 inhibits the activity of cyclin dependent kinases (CDKs) preventing cell cycle transition from G 1 to S phase.…”

Peer Review #2 of "Sclerostin promotes human dental pulp cells senescence (v0.1)"

“…The p53-mediated response to DNA damage, oxidants and hypoxia induces the expression of p21, leading to cellular senescence by inhibiting the activity of cyclin dependent kinases (Muthna et al, 2010;Tonnessen-Murray, Lozano & Jackson, 2017). Our study showed that senescent human dental pulp and subculture-induced senescent HDPCs exhibited higher expression levels of p16, p53 and p21.…”