Expanding the reach of the p53 tumor suppressor network

Abstract

Lying at the heart of most human cancers is the p53 tumor suppressor pathway. 1 When functional, p53 responds to a wide array of cellular stresses by inducing cell cycle arrest or apoptosis. It also facilitates DNA repair, regulates cell metabolism, blocks angiogenesis and triggers cell senescence. Therefore, it is not surprising that when p53 is mutated an emerging tumor cell, perhaps as a result of the activation of an oncogene, can continuously divide, survive and undergo metastasis. How p53 controls such essential processes to suppress tumorigenesis is primarily based on its ability to transcriptionally regulate an ever-expanding series of downstream target genes. The study by Wang et al. 2 has taken an integrative genomic approach using chromatin immunoprecipitation-coupled sequencing (ChIP-seq) and transcriptome analyses to identify an extensive panel of new target genes that may mediate established p53 activities and less well-characterized p53 functions involved in cell signaling, metabolism, motility and immunity. These findings open new opportunities for advancing our understanding of how the p53 network protects against oncogenesis.We have learned much since the identification of the p53 DNA-binding consensus element (RRRCWWGYYY) 3 and the first recognized p53 responsive gene p21 CIP1 (CDKN1A), 4 which plays a major role in enforcing a G1 cell cycle arrest upon DNA damage. Indeed, there are now approximately 150 genes that have been reportedly regulated by the p53 tumor suppressor. The degree to which each of these genes has been validated as a bona fide target is variable, raising an important question as to their relevancy within the p53 network. In addition to p21 CIP1 , some other well-established targets that have been genetically and biochemically validated include Mdm2 (an essential negative regulator of p53) and PUMA (encoding pro-apoptotic BH3-only protein). Each of these genes harbors variations on the theme of the p53 consensus site within their promoter-regulatory regions. Some have higher-affinity sites and are more responsive, whereas others have lower-affinity sites and are less responsive to p53. Therefore, the level of p53 protein could dictate the response, as elegantly shown by Prives and co-workers 5 using conditional expression cell models. Further influencing the capacity of a target to respond to p53 are the surrounding promoter sequences (NB, some elements are located downstream within introns), the cell type (e.g., fibroblasts versus lymphocytes) and the magnitude and form of cell stress (e.g., DNA damage versus oncogenemediated hyperproliferation).We have also learned that not all p53 mutations are created equal. Initial studies focused on the hotspot mutants (e.g., R175H) that contain a missense mutation in the DNA-binding domain. In general, these mutants are incompetent for binding to DNA and activating downstream target genes. There are now more than 28 000 TP53 mutations that have been detected in human cancers (IARC TP53 Database). 6 Some mutations (e.g., R175P) comprom...

Setdb1, a novel interactor of ΔNp63, is involved in breast tumorigenesis

“…TP63 is a transcription factor belonging to the p53 gene family, which includes p73 and p53 [ 23 – 25 ]. p53 is the best studied member of the family, showing a complex genes activation programs from DNA damage repair [ 26 – 29 ], stemness and lineage determination [ 30 , 31 ], autophagy [ 32 , 33 ], mitochondria, metabolism and ROS regulation [ 34 – 36 ].…”

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

“…The members of the p53 family, p53, p63 and p73 have been shown to encompass overlapping target genes, interact with one another [146] and play similar biological roles [147-149]. These include common roles in the protection of the reproductive system [150-152], in development [153-159], aging [160, 161], cell death [162-164], cancer [159, 165-167], redox regulation [161, 168, 169], and metabolism [168, 170, 171].…”

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

“…15 Much of the research in the quest for E3 inhibitors has been finalized for the p53-HDM2 pathway since p53 is an extremely powerful transcription factor crucial in DNA damage response. [16][17][18][19][20][21] Here, the cellular defense to DNA damage is based on sensors and effectors that activates the cell death pathway, [22][23][24] via p53 [25][26][27][28][29] or its family members. [30][31][32][33][34][35][36][37] Like for our recent Itch inhibitor screening, 14 we believe that in a near future innovative E3 inhibitors will be developed.…”