Cell cycle regulation: p53-p21-RB signaling

Abstract

The retinoblastoma protein RB and the transcription factor p53 are central tumor suppressors. They are often found inactivated in various tumor types. Both proteins play central roles in regulating the cell division cycle. RB forms complexes with the E2F family of transcription factors and downregulates numerous genes. Among the RB-E2F target genes, a large number code for key cell cycle regulators. Their transcriptional repression by the RB-E2F complex is released through phosphorylation of RB, leading to expression of the cell cycle regulators. The release from repression can be prevented by the cyclin-dependent kinase inhibitor p21/CDKN1A. The CDKN1A gene is transcriptionally activated by p53. Taken together, these elements constitute the p53-p21-RB signaling pathway. Following activation of p53, for example by viral infection or induction of DNA damage, p21 expression is upregulated. High levels of p21 then result in RB-E2F complex formation and downregulation of a large number of cell cycle genes. Thus, p53-dependent transcriptional repression is indirect. The reduced expression of the many regulators leads to cell cycle arrest. Examination of the p53-p21-RB targets and genes controlled by the related p53-p21-DREAM signaling pathway reveals that there is a large overlap of the two groups. Mechanistically this can be explained by replacing RB-E2F complexes with the DREAM transcriptional repressor complex at E2F sites in target promoters. In contrast to RB-E2F, DREAM can downregulate genes also through CHR transcription factor binding sites. This results in a distinct gene set controlled by p53-p21-DREAM signaling independent of RB-E2F. Furthermore, RB has non-canonical functions without binding to E2F and DNA. Such a role of RB supporting DREAM formation may be exerted by the RB-SKP2-p27-cyclin A/E-CDK2-p130-DREAM link. In the current synopsis, the mechanism of regulation by p53-p21-RB signaling is assessed and the overlap with p53-p21-DREAM signaling is examined.

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

“…p21 is furthermore transcriptionally inhibited by a Myc-Miz complex [ 102 , 103 ] and activated by Smad/FoxO complexes in response to TGF beta stimulation [ 104 ]. The regulation of p16INK4A, p14/p14ARF/p19ARFArf, and p21 are reviewed in detail elsewhere [ 105 , 106 , 107 , 108 , 109 , 110 ].…”

Cell cycle progression defects and impaired DNA damage signaling drive enlarged cells into senescence

“…Because p53 plays an important role in driving cell cycle arrest and damage repair in response to DNA damage [13, 21, 28, 45], we asked whether excess cell size causes increased sensitivity to DNA damaging agents, which was recently reported in palbociclibtreated cells [11]. We found that the proliferation of enlarged cells released from G 1 into a low dose of doxorubicin ( Figure 6A-6B ) or camptothecin ( Figure 6C-6D ) is stunted compared to size-constrained cells, indicating that DNA damage sensitivity following prolonged G 1 arrest is a consequence of increased cell size and not the arrest itself.…”

“…Thus, DNA replication machinery is not limiting for proliferation in excessively large cells. Because p21—which should repress E2F gene expression through the inhibition of cyclin:Cdk complexes [13]— is elevated in enlarged cells, this suggests that opposing mechanisms drive E2F protein expression. This may be related to the recent observation that Rb concentrations are reduced as cells grow larger [19, 20].…”

“…In mammalian cells, senescence induction typically requires one of two signaling axes: the Rb pathway or the p53/p21 pathway [13]. Rb is a cell cycle inhibitor that binds E2F-family transcription factors to inhibit the transcription of G 1 /S cyclins and components of the DNA replication apparatus [14], thereby blocking cell cycle entry.…”

Virus-Mediated Inhibition of Apoptosis in the Context of EBV-Associated Diseases: Molecular Mechanisms and Therapeutic Perspectives

“…EBNA-3C has the ability to interfere with intracellular p53-mediated signaling [126]. p53, the transcription factor responsible for tumor suppression, is widely described in the literature both as a cell cycle regulator and as a potent pro-apoptotic agent [127][128][129][130][131][132]. p53 may promote the expression of the pro-apoptotic members of Bcl-2 family [130] The intracellular signaling network dependent on p53 includes Puma [133], Bim [134], Bid [135], Bax [136,137], and Bak [138,139].…”