ASPP proteins specifically stimulate the apoptotic function of p53.
TL;DR: The expression of ASPP is frequently downregulated in human breast carcinomas expressing wild-type p53 but not mutant p53, therefore, ASPP regulate the tumor suppression function of p53 in vivo.
About: This article is published in Molecular Cell.The article was published on 2001-10-26 and is currently open access. It has received 681 citations till now. The article focuses on the topics: Bcl-2-associated X protein & Transactivation.
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TL;DR: Understanding the complex mechanisms that regulate whether or not a cell dies in response to p53 will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.
Abstract: Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.
3,242 citations
TL;DR: Deregulated cell proliferation provides a minimal 'platform' necessary to support further neoplastic progression and should be targeted withroit targeting to have potent and specific therapeutic consequences.
Abstract: Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression Adroit targeting of these critical events should have potent and specific therapeutic consequences
3,151 citations
TL;DR: This Review focuses on recent advances in the understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.
Abstract: One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21WAF1/Cip1) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.
2,247 citations
TL;DR: What are the molecular mechanisms of tumour resistance to apoptosis and how can the authors use this knowledge to resensitize tumour cells to cancer therapy?
Abstract: Every cell in a multicellular organism has the potential to die by apoptosis, but tumour cells often have faulty apoptotic pathways. These defects not only increase tumour mass, but also render the tumour resistant to therapy. So, what are the molecular mechanisms of tumour resistance to apoptosis and how can we use this knowledge to resensitize tumour cells to cancer therapy?
1,948 citations
TL;DR: It is proposed that antirepression, the release of p53 from repression by factors such as Mdm2 and MdmX, is a key step in the physiological activation of p 53.
1,503 citations
Cites background from "ASPP proteins specifically stimulat..."
...ASPP1 and ASPP2 enhance the proapoptotic function of p53 by selectively promoting the binding of p53 to proapoptotic gene targets such as BAX, PUMA, and PIG3 (Samuels-Lev et al., 2001)....
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Book•
01 Jan 1988
TL;DR: A second edition of Antibodies: A Laboratory Manual is being published in September 2013, Revised, extended and updated by Edward Greenfield of the Dana-Farber Cancer Center, the material has been recast with extensive new information and new chapters have been added.
Abstract: ince its publication in 1988, Antibodies: A Laboratory Manual, by Harlow and Lane, has become a classic, an essential resource for molecular biology, immunology, and cell culture labs. In order to keep the book in print, Cold Spring Harbor Laboratory Press eventually produced the paperback edition currently available for sale. Now, after 25 years, a second edition is being published in September 2013. Revised, extended and updated by Edward Greenfield of the Dana-Farber Cancer Center, the material has been recast with extensive new information and new chapters have been added. The new edition provides clear, authoritative, current and up-to-date protocols with background information and troubleshooting advice. The book is an invaluable resource for all those engaged in antibody research and development.
22,254 citations
TL;DR: Some of the key developments leading to the current state of knowledge in p53 research are presented and how they either shed light on or add to the complexities of p53 are discussed.
Abstract: As the tale of p53 unfolds, it becomes ever more intriguing. Although our understanding of the critical and complex roles played by p53 is progressing rapidly, new findings continue to pose new paradoxes. Here we present some of these recent advances in p53 research and discuss how they either shed light on or add to the complexities of p53. Therefore, we only briefly summarize some of the key developments leading to our current state of knowledge. For further information, the reader is referred to several excellent reviews that have focused on p53 research (see Donehower and Bradley 1993; Levine 1993; Greenblatt et al. 1994; Oren 1994; Prives 1994; Kinzler and Vogelstein 1996).
2,445 citations
TL;DR: The crystal structure of the p53 core domain bound to the 53BP2 protein revealed that the SH3 domain binds the L3 loop of p53 in a manner distinct from that of previously characterized SH3-polyproline peptide complexes, and provides evidence that the 53 BP2-p53 complex forms in vivo and may have a critical role in the p 53 pathway of tumor suppression.
Abstract: Mutations in the p53 tumor suppressor are among the most frequently observed genetic alterations in human cancer and map to the 200-amino acid core domain of the protein. The core domain contains the sequence-specific DNA binding activity and the in vitro 53BP2 protein binding activity of p53. The crystal structure of the p53 core domain bound to the 53BP2 protein, which contains an SH3 (Src homology 3) domain and four ankyrin repeats, revealed that (i) the SH3 domain binds the L3 loop of p53 in a manner distinct from that of previously characterized SH3-polyproline peptide complexes, and (ii) an ankyrin repeat, which forms an L-shaped structure consisting of a β hairpin and two α helices, binds the L2 loop of p53. The structure of the complex shows that the 53BP2 binding site on the p53 core domain consists of evolutionarily conserved regions that are frequently mutated in cancer and that it overlaps the site of DNA binding. The six most frequently observed p53 mutations disrupt 53BP2 binding in vitro. The structure provides evidence that the 53BP2-p53 complex forms in vivo and may have a critical role in the p53 pathway of tumor suppression.
574 citations
TL;DR: Using the yeast two-hybrid system, two previously uncharacterized human proteins, designated 53BP1 and 53BP2, that bind to p53 are identified, suggesting that binding is dependent on p53 conformation.
Abstract: p53 is a tumor-suppressor protein that can activate and repress transcription. Using the yeast two-hybrid system, we identified two previously uncharacterized human proteins, designated 53BP1 and 53BP2, that bind to p53. 53BP1 shows no significant homology to proteins in available databases, whereas 53BP2 contains two adjacent ankyrin repeats and a Src homology 3 domain. In vitro binding analyses indicate that both of these proteins bind to the central domain of p53 (residues 80-320) required for site-specific DNA binding. Consistent with this finding, p53 cannot bind simultaneously to 53BP1 or 53BP2 and to a DNA fragment containing a consensus p53 binding site. Unlike other cellular proteins whose binding to p53 has been characterized, both 53BP1 and 53BP2 bind to the wild-type but not to two mutant p53 proteins identified in human tumors, suggesting that binding is dependent on p53 conformation. The characteristics of these interactions argue that 53BP1 and 53BP2 are involved in some aspect of p53-mediated tumor suppression.
446 citations
Journal Article•
TL;DR: The combined use of laser capture microdissection and high-throughput cDNA microarrays to monitor in vivo gene expression levels in purified normal, invasive, and metastatic breast cell populations from a single patient is reported.
Abstract: The development and use of molecular-based therapy for breast cancer and other human malignancies will require a detailed molecular genetic analysis of patient tissues. The recent development of laser capture microdissection and high density cDNA arrays now provides a unique opportunity to generate gene expression profiles of cells from various stages of tumor progression as it occurs in the actual neoplastic tissue milieu. We report the combined use of laser capture microdissection and high-throughput cDNA microarrays to monitor in vivo gene expression levels in purified normal, invasive, and metastatic breast cell populations from a single patient. These in vivo gene expression profiles were verified by real-time quantitative PCR and immunohistochemistry. The combined use of laser capture microdissection and cDNA microarray analysis provides a powerful new approach to elucidate the in vivo molecular events surrounding the development and progression of breast cancer and is generally applicable to the study of malignancy.
425 citations