Withdrawal: Tumor suppressor SMAR1 activates and stabilizes p53 through its arginine-serine-rich motif (original) (raw)
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International Journal of Cancer, 2003
The tumor-suppressor p53 is a multifunctional protein mainly responsible for maintaining genomic integrity. p53 induces its tumor-suppressor activity by either causing cell-cycle arrest (G1/S or G2/M) or inducing cells to undergo apoptosis. This function of wild-type p53 as “guardian of the genome” is presumably achieved by forming molecular complexes with different DNA targets as well as by interacting with a number of cellular proteins, e.g., Mdm2, Gadd45, p21, 14-3-3σ, Bax and Apaf-1. Upon activation, p53 activates p21, which in turn controls the cell cycle by regulating G1 or G2 checkpoints. Here, we report SMAR1 as one such p53-interacting protein that is involved in delaying tumor progression in vivo as well as in regulating the cell cycle. SMAR1 is a newly identified MARBP involved in chromatin-mediated gene regulation. The SMAR1 gene encodes at least 2 alternatively spliced variants: SMAR1L (the full-length form) and SMAR1S (the shorter form). We report that expression of SMAR1S, but not of SMAR1L, mRNA was decreased in most of the human cell lines examined, suggesting selective silencing of SMAR1S. Overexpression of SMAR1S in mouse melanoma cells (B16F1) and their subsequent injection in C57BL/6 mice delays tumor growth. Exogenous SMAR1S causes significant retardation of B16F1 cells in the G2/M phase of the cell cycle compared to SMAR1L. SMAR1S activates p53-mediated reporter gene expression in mouse melanoma cells, breast cancer cells (MCF-7) and p53 null cells (K562), followed by activation of its downstream effector, p21. We further demonstrate that SMAR1 physically interacts and colocalizes with p53. These data together suggest that SMAR1 is the only known MARBP that delays tumor progression via direct activation and interaction with tumor-suppressor p53. © 2002 Wiley-Liss, Inc.
The regulation of p53 growth suppression
Cell Cycle …, 2001
T he p53 tumor suppressor protein plays a pivotal role in the cellular response to stress. A variety of stress signals trigger accumulation and activation of p53 to halt the cell cycle and to prevent replication of damaged DNA. The p53 protein is required for a proper G1 arrest, it is essential for maintaining the G2 arrest, and it contributes to the mitotic spindle checkpoint. p53 exerts these actions by inducing multiple target genes. Under defined conditions, p53 induces programmed cell death by mechanisms that are partially understood and involve a combination of transcriptional dependent and -independent activities. The choice between arrest and cell death depends on the final integration of antagonistic signals. These include the type and intensity of the stress signal, the spectrum of the target genes induced, the type of cell and its oncogenic status, and the presence of growth and survival factors. The stability of the p53 protein and its activities are tightly regulated by many factors among which the Mdm2 proto-oncoprotein is the central player. Inhibitory effects of Mdm2 on p53 stability and activities are modulated by multiple mechanisms including post-translational modifications of p53 and Mdm2 and by other interacting proteins. Importantly, p53 is also regulated at the level of its sub-cellular localization. Sequestration of p53 into the cytoplasm is sufficient for its inhibition. In contrast, accumulation of p53 in the nucleus induces its transcriptional activity. This activity can be further enhanced by specific post-translational modifications and by recruitment of p53 into nuclear bodies. We discuss current views on the regulation of p53 and its growth inhibitory activities. 221 Cdc14 ND Ser-315 Unknown 222 C. Acetylation p300/CBP IR, UV Lys-373, Lys-382 Enhanced SST and stability 166,223 PCAF UV Lys-320 Enhanced SST 166 D. Sumoylation Unknown enzyme ND Lys-386 Enhanced SST 59-61 E. Ribosylation PARP IR Poly(ADP)ribosylation Enhanced SST and stability 224-225 Abbreviation: SST -Sequence specific transactivation, IR -ionizing radiation, ND -not determined, IFN -interferon, dsRNA -double stranded RNA
Links between Tumor Suppressors
Cell, 2003
s, Activin, and Nodal, are transduced by Smad2 or 1 Department of Histology, Microbiology, and Smad3, whereas BMPs are transduced by Smad1 (Mas-Medical Biotechnologies sagué , 2000). Section of Histology and Embryology Once activated, the Smads translocate into the nu-University of Padua cleus where they control gene expression in association viale Colombo 3 with Smad4 and partner transcriptional regulators (Mas-35121 Padua sagué , 2000). How the Smads recognize and properly Italy activate a specific promoter is not fully understood. In 2 Department of Experimental Oncology part, specificity depends on the differential expression European Institute of Oncology of distinct Smad partners in distinct cell types; however, via Ripamonti 435 several inputs can profoundly modify both the percep-20141 Milan tion of the TGF- signal and its biological output (Mas-Italy sagué , 2000). Understanding how this transcriptional 3 Department of Biology plasticity is attained is central for embryonic develop-University of Modena and Reggio Emilia ment and cancer. For example, most carcinomas have via Campi 213 selectively lost the growth arrest response and gained 41100 Modena metastatic abilities in response to TGF- (Wakefield and Italy Roberts,
Bulletin du cancer
p53 was originally considered to be a nuclear oncogene, but several convergent lines of research have indicated that the wild-type gene functions as a tumor suppressor gene negatively regulating the cell cycle. Mutations in the p53 gene have been detected in many tumor types and seem to be the most common genetic alterations in human cancer. In this preliminary study, sera of 92 patients (pts) with breast disease were analyzed for the presence of the mutant p53 protein (m p53) with a selective immunoenzyme assay employing a monoclonal antibody (PAb 240) specific for the majority of mammalian m p53 but not for the wild-type protein. Of the 10 patients with benign breast disease, only two (20%) showed detectable m p53 levels in the serum. In the breast cancer group, sera from 7 of the 30 pts (23%) without lymph node involvement were positive for m p53, as were 7 out of the 45 pts (15%) with metastatic lymph nodes and I out of the 7 pts (14%) with disseminated disease. The specifity of m p53 assay evaluated in 20 healthy 26 MicelU et al.
The p53 Tumor Suppressor Gene: From Molecular Biology to Clinical Investigation
Annals of the New York Academy of Sciences, 2006
The tumor suppressor p53 is a phosphoprotein barely detectable in the nucleus of normal cells. Upon cellular stress, particularly that induced by DNA damage, p53 can arrest cell cycle progression, thus allowing the DNA to be repaired; or it can lead to apoptosis. These functions are achieved, in part, by the transactivational properties of p53, which activate a series of genes involved in cell cycle regulation. In cancer cells bearing a mutant p53, this protein is no longer able to control cell proliferation, resulting in inefficient DNA repair and the emergence of genetically unstable cells. The most common changes of p53 in human cancers are point missense mutations within the coding sequences of the gene. Such mutations are found in all major histogenetic groups, including cancers of the colon (60%), stomach (60%), breast (20%), lung (70%), brain (40%), and esophagus (60%). It is estimated that p53 mutations are the most frequent genetic event in human cancers, accounting for more than 50% of cases. One of the most striking features of the inactive mutant p53 protein is its increased stability (half-life of several hours, compared to 20 min for wild-type p53) and its accumulation in the nucleus of neoplastic cells. Therefore, positive immunostaining is indicative of abnormalities of the p53 gene and its product. Several studies have shown that p53 mutations are associated with short survival in colorectal cancer, but the use of p53 as a tumoral marker is still a matter of debate.
The 1993 Walter Hubert Lecture: the role of the p53 tumour-suppressor gene in tumorigenesis
1994
The p53 tumour-suppressor gene is mutated in 60% of human tumours, and the product of the gene acts as a suppressor of cell division. It is thought that the growth-suppressive effects of p53 are mediated through the transcriptional transactivation activity of the protein. Overexpression of the p53 protein results either in arrest in the GI phase of the cell cycle or in the induction of apoptosis. Both the level of the protein and its transcriptional transactivation activity increase following treatment of cells with agents that damage DNA, and it is thought that p53 acts to protect cells against the accumulation of mutations and subsequent conversion to a cancerous state. The induction of p53 levels in cells exposed to gamma-irradiation results in cell cycle arrest in some cells (fibroblasts) and apoptosis in others (thymocytes). Cells lacking p53 have lost this cell cycle control and presumably accumulate damage-induced mutations that result in tumorigenesis. Thus, the role of p53 in suppressing tumorigenesis may be to rescue the cell or organism from the mutagenic effects of DNA damage. Loss of p53 function accelerates the process of tumorigenesis and alters the response of cells to agents that damage DNA, indicating that successful strategies for radiation therapy may well need to take into account the tissue of origin and the status of p53 in the tumour.