Cell Death & Differentiation

Levine, Arnold J.

doi: 10.1038/s41418-022-00986-1pmid: 35383291

Liu, Yanqing; Gu, Wei

doi: 10.1038/s41418-022-00943-ypmid: 35087226

Although the conventional activities of p53 such as cell cycle arrest, senescence, and apoptosis are well accepted as the major checkpoints in stress responses, accumulating evidence implicates the importance of other tumor suppression mechanisms. Among these unconventional activities, an iron-dependent form of non-apoptotic cell death, termed ferroptosis, attracts great interest. Unlike apoptotic cell death, activation of p53 alone is not sufficient to induce ferroptosis directly; instead, through its metabolic targets, p53 is able to modulate the ferroptosis response in the presence of ferroptosis inducers such as GPX4 inhibitors or high levels of ROS. Here, we review the role of ferroptosis in p53-mediated tumor suppression, with a focus on what cellular factors are critical for p53-dependent ferroptosis during tumor suppression and how p53 modulates both the canonical (GPX4-dependent) and the non-canonical (GPX4-independent) ferroptosis pathways. We also discuss the possibility of targeting p53-mediated ferroptotic responses for the treatment of human cancers and potentially, other diseases.[graphic not available: see fulltext]

Wang, Zilu; Strasser, Andreas; Kelly, Gemma L.

doi: 10.1038/s41418-022-00962-9pmid: 35332311

Mutations in the TP53 tumour suppressor gene are found in ~50% of human cancers [1–6]. TP53 functions as a transcription factor that directly regulates the expression of ~500 genes, some of them involved in cell cycle arrest/cell senescence, apoptotic cell death or DNA damage repair, i.e. the cellular responses that together prevent tumorigenesis [1–6]. Defects in TP53 function not only cause tumour development but also impair the response of malignant cells to anti-cancer drugs, particularly those that induce DNA damage [1–6]. Most mutations in TP53 in human cancers cause a single amino acid substitution, usually within the DNA binding domain of the TP53 protein. These mutant TP53 proteins are often expressed at high levels in the malignant cells. Three cancer causing attributes have been postulated for mutant TP53 proteins: the inability to activate target genes controlled by wt TP53 (loss-of-function, LOF) that are critical for tumour suppression, dominant negative effects (DNE), i.e. blocking the function of wt TP53 in cells during early stages of transformation when mutant and wt TP53 proteins are co-expressed, and gain-of-function (GOF) effects whereby mutant TP53 impacts diverse cellular pathways by interacting with proteins that are not normally engaged by wt TP53 [1–6]. The GOF effects of mutant TP53 were reported to be essential for the sustained proliferation and survival of malignant cells and it was therefore proposed that agents that can remove mutant TP53 protein would have substantial therapeutic impact [7–9]. In this review article we discuss evidence for and against the value of targeting mutant TP53 protein for cancer therapy.

Osterburg, Christian; Dötsch, Volker

doi: 10.1038/s41418-022-00975-4pmid: 35314772

The p53 protein family is the most studied protein family of all. Sequence analysis and structure determination have revealed a high similarity of crucial domains between p53, p63 and p73. Functional studies, however, have shown a wide variety of different tasks in tumor suppression, quality control and development. Here we review the structure and organization of the individual domains of p63 and p73, the interaction of these domains in the context of full-length proteins and discuss the evolutionary origin of this protein family.[graphic not available: see fulltext]FactsDistinct physiological roles/functions are performed by specific isoforms.The non-divided transactivation domain of p63 has a constitutively high activity while the transactivation domains of p53/p73 are divided into two subdomains that are regulated by phosphorylation.Mdm2 binds to all three family members but ubiquitinates only p53.TAp63α forms an autoinhibited dimeric state while all other vertebrate p53 family isoforms are constitutively tetrameric.The oligomerization domain of p63 and p73 contain an additional helix that is necessary for stabilizing the tetrameric states. During evolution this helix got lost independently in different phylogenetic branches, while the DNA binding domain became destabilized and the transactivation domain split into two subdomains.Open questionsIs the autoinhibitory mechanism of mammalian TAp63α conserved in p53 proteins of invertebrates that have the same function of genomic quality control in germ cells?What is the physiological function of the p63/p73 SAM domains?Do the short isoforms of p63 and p73 have physiological functions?What are the roles of the N-terminal elongated TAp63 isoforms, TA* and GTA?

Hoyos, David; Greenbaum, Benjamin; Levine, Arnold J.

doi: 10.1038/s41418-022-00980-7pmid: 35383292

The p53 protein is structurally and functionally divided into five domains. The proline-rich domain is localized at amino acids 55–100. 319 missense mutations were identified solely in the proline domain from human cancers. Six hotspot mutations were identified at amino acids 72, 73, 82, 84, 89, and 98. Codon 72 contains a polymorphism that changes from proline (and African descent) to arginine (with Caucasian descent) with increasing latitudes northward and is under natural selection for pigmentation and protection from UV light exposure. Cancers associated with mutations in the proline domain were considerably enriched for melanomas and skin cancers compared to mutations in other p53 domains. These hotspot mutations are enriched at UV mutational signatures disrupting amino acid signals for binding SH-3-containing proteins important for p53 function. Among the protein–protein interaction sites identified by hotspot mutations were MDM-2, a negative regulator of p53, XAF-1, promoting p53 mediated apoptosis, and PIN-1, a proline isomerase essential for structural folding of this domain.

Engeland, Kurt

doi: 10.1038/s41418-022-00988-zpmid: 35361964

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.[graphic not available: see fulltext]

Thomas, Annabella F.; Kelly, Gemma L.; Strasser, Andreas

doi: 10.1038/s41418-022-00996-zpmid: 35396345

The tumour suppressor TP53 is a master regulator of several cellular processes that collectively suppress tumorigenesis. The TP53 gene is mutated in ~50% of human cancers and these defects usually confer poor responses to therapy. The TP53 protein functions as a homo-tetrameric transcription factor, directly regulating the expression of ~500 target genes, some of them involved in cell death, cell cycling, cell senescence, DNA repair and metabolism. Originally, it was thought that the induction of apoptotic cell death was the principal mechanism by which TP53 prevents the development of tumours. However, gene targeted mice lacking the critical effectors of TP53-induced apoptosis (PUMA and NOXA) do not spontaneously develop tumours. Indeed, even mice lacking the critical mediators for TP53-induced apoptosis, G1/S cell cycle arrest and cell senescence, namely PUMA, NOXA and p21, do not spontaneously develop tumours. This suggests that TP53 must activate additional cellular responses to mediate tumour suppression. In this review, we will discuss the processes by which TP53 regulates cell death, cell cycling/cell senescence, DNA damage repair and metabolic adaptation, and place this in context of current understanding of TP53-mediated tumour suppression.

Lindström, Mikael S.; Bartek, Jiri; Maya-Mendoza, Apolinar

doi: 10.1038/s41418-022-00999-wpmid: 35444234

Despite several decades of intense research focused on understanding function(s) and disease-associated malfunction of p53, there is no sign of any “mid-life crisis” in this rapidly advancing area of biomedicine. Firmly established as the hub of cellular stress responses and tumor suppressor targeted in most malignancies, p53’s many talents continue to surprise us, providing not only fresh insights into cell and organismal biology, but also new avenues to cancer treatment. Among the most fruitful lines of p53 research in recent years have been the discoveries revealing the multifaceted roles of p53-centered pathways in the fundamental processes of DNA replication and ribosome biogenesis (RiBi), along with cellular responses to replication and RiBi stresses, two intertwined areas of cell (patho)physiology that we discuss in this review. Here, we first provide concise introductory notes on the canonical roles of p53, the key interacting proteins, downstream targets and post-translational modifications involved in p53 regulation. We then highlight the emerging involvement of p53 as a key component of the DNA replication Fork Speed Regulatory Network and the mechanistic links of p53 with cellular checkpoint responses to replication stress (RS), the driving force of cancer-associated genomic instability. Next, the tantalizing, yet still rather foggy functional crosstalk between replication and RiBi (nucleolar) stresses is considered, followed by the more defined involvement of p53-mediated monitoring of the multistep process of RiBi, including the latest updates on the RPL5/RPL11/5 S rRNA-MDM2-p53-mediated Impaired Ribosome Biogenesis Checkpoint (IRBC) pathway and its involvement in tumorigenesis. The diverse defects of RiBi and IRBC that predispose and/or contribute to severe human pathologies including developmental syndromes and cancer are then outlined, along with examples of promising small-molecule-based strategies to therapeutically target the RS- and particularly RiBi- stress-tolerance mechanisms to which cancer cells are addicted due to their aberrant DNA replication, repair, and proteo-synthesis demands.[graphic not available: see fulltext]

Kennedy, Margaret C.; Lowe, Scott W.

doi: 10.1038/s41418-022-00989-ypmid: 35361963

Mutation of the TP53 tumor suppressor gene is the most common genetic alteration in cancer, and almost 1000 alleles have been identified in human tumors. While virtually all TP53 mutations are thought to compromise wild type p53 activity, the prevalence and recurrence of missense TP53 alleles has motivated countless research studies aimed at understanding the function of the resulting mutant p53 protein. The data from these studies support three distinct, but perhaps not necessarily mutually exclusive, mechanisms for how different p53 mutants impact cancer: first, they lose the ability to execute wild type p53 functions to varying degrees; second, they act as a dominant negative (DN) inhibitor of wild type p53 tumor-suppressive programs; and third, they may gain oncogenic functions that go beyond mere p53 inactivation. Of these possibilities, the gain of function (GOF) hypothesis is the most controversial, in part due to the dizzying array of biological functions that have been attributed to different mutant p53 proteins. Herein we discuss the current state of understanding of TP53 allele variation in cancer and recent reports that both support and challenge the p53 GOF model. In these studies and others, researchers are turning to more systematic approaches to profile TP53 mutations, which may ultimately determine once and for all how different TP53 mutations act as cancer drivers and whether tumors harboring distinct mutations are phenotypically unique. From a clinical perspective, such information could lead to new therapeutic approaches targeting the effects of different TP53 alleles and/or better sub-stratification of patients harboring TP53 mutant cancers.

Liang, Junnan; Li, Ganxun; Liao, Jingyu; Huang, Zhao; Wen, Jingyuan; Wang, Yu; Chen, Zeyu; Cai, Guangzhen; Xu, Weiqi; Ding, Zeyang; Liang, Huifang; Datta, Pran K.; Chu, Liang; Chen, Xiaoping; Zhang, Bixiang