TopBP1 Mediates Mutant p53 Gain of Function through NF-Y and p63/p73

Abstract

Nearly half of human cancers harbor p53 mutations, which can promote cancerous growth, metastasis, and resistance to therapy. The gain of function of mutant p53 is partly mediated by its ability to form a complex with NF-Y or p63/p73. Here, we demonstrate that TopBP1 mediates these activities in cancer, and we provide both in vitro and in vivo evidence to support its role. We show that TopBP1 interacts with p53 hot spot mutants and NF-YA and promotes mutant p53 and p300 recruitment to NF-Y target gene promoters. TopBP1 also facilitates mutant p53 interaction with and inhibition of the transcriptional activities of p63/p73. Depletion of TopBP1 in mutant p53 cancer cells leads to downregulation of NF-Y target genes cyclin A and Cdk1 and upregulation of p63/p73 target genes such as Bax and Noxa. Mutant p53-mediated resistance to chemotherapeutic agents depends on TopBP1. The growth-promoting activity of mutant p53 in a xenograft model also requires TopBP1. Thus, TopBP1 mediates mutant p53 gain of function in cancer. Since TopBP1 is often overexpressed in cancer cells and is recruited to cooperate with mutant p53 for tumor progression, TopBP1/ mutant p53 interaction may be a new therapeutic target in cancer.The tumor suppressor protein p53 generally functions through a specific DNA binding activity. Mutations of p53 are found in almost half of human cancers. Most of these mutations occur within the DNA-binding domain of p53, destroying its specific DNA binding activity. It is also well recognized that mutant p53 (mutp53) acquires new functions (gain of function) in promoting cancer cell proliferation, metastasis, genomic instability, and resistance to chemotherapy (33). The combined effects of both loss of tumor suppression and newly gained oncogenic properties may explain the high prevalence of mutp53 in human cancers.There are several potential mechanisms for mutp53 gain of function in transcriptional regulation. mutp53 can interact with NF-Y, a heterotrimeric transcription factor that recognizes the CCAAT consensus motif and regulates many cell cycle-related genes such as cyclin A, cyclin B, Cdk1, Cdc25C, etc. (7). Through the interaction, mutp53 and p300 are recruited to NF-Y target gene promoters and are responsible for aberrant expression of the above-mentioned NF-Y target genes and consequently abnormal proliferation. mutp53 can form a complex with p63/p73 and block the DNA binding activities of p63 and p73 and therefore inactivate their proapoptotic functions (9, 30, 39). mutp53 was also reported to bind non-B DNA in a DNA structure-selective manner rather than a sequence-specific manner. This binding was proposed to be the basis for its interaction with the matrix attachment region resulting in inhibition of the transcription factor recruitment and transcriptional repression (12). The full scope of mutp53 in carcinogenesis remains to be explored. Understanding its mechanistic aspect would be imperative for us to devise badly needed therapeutic strategies targeting the mutp53 gain of function in cancer.TopBP...

Mutant p53 interactome identifies nardilysin as a p53R273H‐specific binding partner that promotes invasion

“…The p53R273H protein mediates invasion towards EGF through its ability to inactivate p63, while, as shown here, invasion to HB-EGF can be mediated through a new and highly specific biochemical interaction with NRD1. Our observations that mutant p53 can cooperate with NRD1 to promote invasion are consistent with several recent studies [10][11][12]14,[16][17][18]32] that demonstrated a neomorphic ability of mutant p53 to promote invasion. One mechanism underlying this gain of function of mutant p53 is an inhibition of the p53 family member p63, thereby promoting invasion responses to two important growth factors; EGF [11] and tumour growth factor-b [10].…”

“…Mechanisms underlying the oncogenic nature of mutant p53 include interaction or regulation of other transcription factors including p63, p73, NF-Y and VDR [12][13][14][15] or additional binding proteins such as TOPBP1, ANKRD11 and PIN1 [16][17][18]. Nearly all of the large number of interacting proteins reported in IARC p53 database [2] bind to wt-p53 and are therefore not good candidates for the neomorphic mutant hypothesis.…”

Pla2g16 phospholipase mediates gain-of-function activities of mutant p53

“…Other mechanisms of mutant p53 GOF include mutant-p53 complexes with Smad that fuel TGF-β-induced metastasis (7) and integrin recycling (8). Additionally, mutant p53 interacts with the vitamin D receptor and converts vitamin D into an antiapoptotic agent (9)(10)(11)(12)(13)(14). More recently, mutant p53 was reported to form transcriptional complexes on promoters of genes encoding several enzymes of the Mevalonate pathway, which increases metastasis of breast cancer cells (9).…”

EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression

“…To confirm the functional link between ZDHHC5 and p53, we examined whether mutant p53 modulated ZDHHC5 expression, as most cancer-associated p53 mutations are associated with a loss of its transcriptional activity. Mutant p53 was capable of physical interaction with the transcription factor NF-Y; the gain-offunction induced by this protein complex was independent of the type of p53 mutation (27,28). Moreover, this interaction resulted in aberrant upregulation of ZDHHC5, whose promoter contains four potential NF-Y-binding sites.…”

“…2B). The most common frameshift and missense mutations in the p53 gene result in a gain of function and interaction of p53 with nuclear transcription factor (NF)-Y, which leads to aberrant transcriptional regulation of oncogenic factors (27,28). The 1-kb upstream region of the ZDHHC5 promoter contained four potential NF-Ybinding sites ( Supplementary Fig.…”