Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

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Cancer development is a multistage process that results from the step-wise acquisition of somatic alterations in diverse genes. Recent studies indicate that caveolin-1 expression correlates with the level of oncogenic transformation in NIH3T3 cells, suggesting that caveolin in caveolae may regulate normal cell proliferation. In order to better understand potential functions of caveolin-1 in cancer development, we have studied expression levels of caveolin-1 in human breast cancer cells, and have found that caveolin expression is signi®cantly reduced in human breast cancer cells compared with their normal mammary epithelial counterparts. When the caveolin cDNA linked to the CMV promoter is transfected into human mammary cancer cells having no detectable endogenous caveolin, overexpression of caveolin-1 resulted in substantial growth inhibition, as seen by the 50% decrease in growth rate and by *l5-fold reduction in colony formation in soft agar. In addition, characterization of caveolin-1 expression during cell cycle progression indicates that expression of a-caveolin-1 is regulated during cell cycle. Furthermore p53-de®cient cells showed a loss in caveolin expression. In summary, the overall expression patterns, its ability to inhibit tumor growth in culture, its regulation during the cell cycle, and the loss of expression in p53-de®cient cells all are consistent with an important growth regulating function for caveolin-1 in normal human mammary cells, that needs to be repressed in oncogenic transformation and tumor cell growth.

Oncogenes Neu/HER2/ErbB2 and Ras can induce mammary tumorigenesis via upregulation of cyclin D1. One major regulatory mechanism in these oncogenic signaling pathways is phosphorylation of serines or threonines preceding proline (pSer/Thr-Pro). Interestingly, the pSer/Thr-Pro motifs in proteins exist in two completely distinct cis and trans conformations, whose conversion is catalyzed specifically by the essential prolyl isomerase Pin1. By isomerizing pSer/Thr-Pro bonds, Pin1 can regulate the conformation and function of certain phosphorylated proteins. We have previously shown that Pin1 is overexpressed in breast tumors and positively regulates cyclin D1 by transcriptional activation and posttranslational stabilization. Moreover, in Pin1 knockout mice, mammary epithelial cells fail to undergo massive proliferation during pregnancy, as is the case in cyclin D1 null mice. These results indicate that Pin1 is upregulated in breast cancer and may be involved in mammary tumors. However, the mechanism of Pin1 overexpression in cancer and its significance in cell transformation remain largely unknown. Here we demonstrate that PIN1 expression is mediated by the transcription factor E2F and enhanced by c-Neu and Ha-Ras via E2F. Furthermore, overexpression of Pin1 not only confers transforming properties on mammary epithelial cells but also enhances the transformed phenotypes of Neu/Ras-transformed mammary epithelial cells. In contrast, inhibition of Pin1 suppresses Neu-and Ras-induced transformed phenotypes, which can be fully rescued by overexpression of a constitutively active cyclin D1 mutant that is refractory to the Pin1 inhibition. Thus, Pin1 is an E2F target gene that is essential for the Neu/Ras-induced transformation of mammary epithelial cells through activation of cyclin D1.Phosphorylation of proteins on serine/threonine residues preceding proline (pSer/Thr-Pro) is a key regulatory mechanism for the control of cell proliferation and transformation (6,18,22,31). For example, oncogenic Neu/Ras signaling has shown to lead to activation of various Pro-directed protein kinases, which eventually enhance transcription of the cyclin D1 gene via multiple transcription factors, including E2F, cjun/AP-1, and ␤-catenin/T-cell factor (TCF) (1,3,17,26,28,47). In addition to transcriptional activation, cyclin D1 is regulated by posttranslational modifications. Phosphorylation of cyclin D1 on the Thr286-Pro site by glycogen synthase kinase 3␤ (GSK-3␤) enhances its nuclear export and subsequent degradation (2, 9, 10).Cyclin D1 has been shown to play a pivotal role in the development of cancer, especially breast cancer. Overexpression of cyclin D1 is found in 50% of patients with breast cancer (5, 15). Importantly, overexpression of cyclin D1, especially the mutant cyclin D1 T286A , can transform fibroblasts (2, 20). In contrast, inhibition of cyclin D1 expression causes growth arrest in tumor cells (4,11,26,45). Furthermore, transgenic overexpression of cyclin D1 in the mouse mammary gland leads to mammary hyperplasia and event...

Tumour-suppressor genes are indispensable for the maintenance of genomic integrity. Recently, several of these genes, including p53, PTEN, RB1 and ARF, have been implicated in immune responses and inflammatory diseases. In particular, the p53 tumour-suppressor pathway is involved in crucial aspects of tumour immunology and in homeostatic regulation of immune responses. Other studies have identified roles for p53 in various cellular processes, including metabolism and stem cell maintenance. Here, we discuss the emerging roles of p53 and other tumour-suppressor genes in tumour immunology as well as in additional immunological settings, such as virus infection. This relatively unexplored area could yield important insights into the homeostatic control of immune cells in health and disease, and facilitate the development of more effective immunotherapies. Consequently, tumour-suppressor genes are emerging as potential guardians of immune integrity.

The p53 tumor suppressor gene can induce either apoptosis or a permanent growth arrest (also termed senescence) phenotype in response to cellular stresses. We show that the increase in intracellular reactive oxygen species (ROS) associated with the magnitude of p53 protein expression correlated with the induction of either senescence or apoptosis in both normal and cancer cells. ROS inhibitors ameliorated both p53-dependent cell fates, implicating ROS accumulation as an effector in each case. The absence of Bax or PUMA strongly inhibited both p53-induced apoptosis and ROS increase, indicating an important role these p53 targets affecting mitochondrial function genes in p53-mediated ROS accumulation. Moreover, physiological p53 levels in combination with an exogenous ROS source were able to convert a p53 senescence response into apoptosis. All of these findings establish a critical role of ROS accumulation and mitochondrial function in p53-dependent cell fates and show that other ROS inducers can collaborate with p53 to influence these fate decisions. Thus, our studies imply that therapeutic agents that generate ROS are more likely to be toxic for normal cells than p53-negative tumor cells and provide a rationale for identifying therapeutic agents that do not complement p53 in ROS generation to ameliorate the cytotoxic side effects in normal cells.The p53 tumor suppressor protein can trigger the onset either of reversible or permanent growth arrest (51, 52) or of apoptosis (27,34). However, the mechanisms involved in the decision between these cellular responses are not well understood. Cell type, the presence of growth factors or oncogenes, the intensity of the stress signal, and the cellular level of p53 have been cited as important factors in determining a specific p53-induced response (7,12,53). Posttranslational modifications of the p53 gene have also been reported to influence the response observed. For example, p53 phosphorylation by different kinases in response to stress can select for arrest or apoptosis, suggesting the involvement of modifiers upstream of the p53 gene (29). Moreover, p53 mutants that can induce growth arrest but not apoptosis, or vice versa, have been identified (12,49,60), which is consistent with the concept that certain p53 gene mutations may cause selective loss of the ability to transactivate certain p53-responsive promoters (35).Several p53-target genes have been reported to be specifically involved in apoptosis. These genes include those encoding KILLER/DR5 (56), Bax (39), IGF-BP3 (6), and, more recently, PIG3 (45), PAG608 (24), PERP (1), Noxa (43), PIDD (33), p53AIP1 (44), APAF-1 (46), ferredoxin reductase (FDXR) (23), and PUMA (41, 57). Some of the genes, like the PIG3 and FDXR genes, are involved in reactive oxygen species (ROS)-related pathways (45). Moreover, apoptosis triggered by p53 has been reported to be dependent on an increase of ROS and the release of apoptotic factors resulting from mitochondrial damage (45).An increase in ROS has independently been implicated in c...

The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1α (DD1α), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1α appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1α-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1α thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses.