Che-1/AATF: A Critical Cofactor for Both Wild-Type- and Mutant-p53 Proteins

Abstract

The p53 protein is a key player in a wide range of protein networks that allow the state of “good health” of the cell. Not surprisingly, mutations of the TP53 gene are one of the most common alterations associated to cancer cells. Mutated forms of p53 (mtp53) not only lose the ability to protect the integrity of the genetic heritage of the cell but also acquire pro-oncogenic functions, behaving like dangerous accelerators of transformation and tumor progression. In recent years, many studies focused on investigating possible strategies aiming to counteract this mutant p53 “gain of function” but the results have not always been satisfactory. Che-1/AATF is a nuclear protein that binds to RNA polymerase II and plays a role in multiple fundamental processes, including control of transcription, cell cycle regulation, DNA damage response, and apoptosis. Several studies showed Che-1/AATF as an important endogenous regulator of p53 expression and activity in a variety of biological processes. Notably, this same regulation was more recently observed also on mtp53. The depletion of Che-1/AATF strongly reduces the expression of mutant p53 in several tumors in vitro and in vivo, making the cells an easier target for chemotherapy treatments. In this mini review, we report an overview of Che-1/AATF functions and discuss a possible role of Che-1/AATF in cancer therapy, with particular regard to its action on p53/mtp53.

Che‐1 is targeted by c‐Myc to sustain proliferation in pre‐B‐cell acute lymphoblastic leukemia

“…In agreement with previous findings [9,30], we found that Che-1 inhibition not only strongly affects BCP-ALL cell growth, implying that it could be involved in leukemia clonal expansion, but also sensitizes BCP-ALL cells to chemotherapeutic treatment. The main function known of Che-1 is to activate gene transcription [31]. RNA-seq experiments in NALM-6 and in a primary BCP-ALL cell line confirmed this role, highlighting how this protein is required for control in the expression of several genes involved in cell growth.…”

“…The main function known of Che‐1 is to activate gene transcription . RNA‐seq experiments in NALM‐6 and in a primary BCP‐ALL cell line confirmed this role, highlighting how this protein is required for control in the expression of several genes involved in cell growth.…”

Human AATF/Che-1 forms a nucleolar protein complex with NGDN and NOL10 required for 40S ribosomal subunit synthesis

“…AATF has been linked to p53-mediated stress response (8). Consequently, to exclude indirect effects of AATF depletion on ribosome biogenesis via its link to the p53 pathway, we also compared the effects of AATF siRNA treatment in p53 wild-type and p53 −/− HCT116 cell lines (26).…”

“…In its function as RNA polymerase II-specific transcription factor, AATF has been previously suggested to bind the promoter region of the TP53 gene, modulating the transcriptional activity of p53 protein and regulating cellular stress responses (5–8). Importantly, we show that the function of AATF in ribosome synthesis is independent of p53.…”

“…Meanwhile, AATF has been linked to many different cellular processes including cell proliferation, DNA damage response and cell cycle control (4). As a transcriptional regulator, AATF plays an important role in stress responses upon DNA damage, including activation of p53 and potentially p21 (5–8). Overexpression of AATF has been observed in several human leukemic cell lines, and, remarkably, depletion of AATF suppresses tumor growth and increases chemotherapy sensitivity of tumors in mouse xenograft models (6,7,9).…”