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Jakob Gebel, Laura M Luh, Daniel Coutandin, Christian Osterburg, Frank Löhr, Birgit Schäfer, Ann-Sophie Frombach, Manuela Sumyk, Lena Buchner, Tobias Krojer, Eidarus Salah, Sebastian Mathea, Peter Güntert, Stefan Knapp, Volker Dötsch
Members of the p53 tumor-suppressor family are expressed as multiple isoforms. Isoforms with an N-terminal transactivation domain are transcriptionally active, while those ones lacking this domain often inhibit the transcriptional activity of other family members. In squamous cell carcinomas, the high expression level of ΔNp63α inhibits the tumor-suppressor function of TAp73β. This can in principle be due to blocking of the promoter or by direct interaction between both proteins. p63 and p73 can hetero-oligomerize through their tetramerization domains and a hetero-tetramer consisting of two p63 and two p73 molecules is thermodynamically more stable than both homo-tetramers...
October 7, 2016: Cell Death and Differentiation
Toshinori Ozaki, Mizuyo Nakamura, Takehiro Ogata, Meijie Sang, Hiroyuki Yoda, Kiriko Hiraoka, Meixiang Sang, Osamu Shimozato
Recently, we have described that siRNA-mediated silencing of runt-related transcription factor 2 (RUNX2) improves anti-cancer drug gemcitabine (GEM) sensitivity of p53-deficient human pancreatic cancer AsPC-1 cells through the augmentation of p53 family TAp63-dependent cell death pathway. In this manuscript, we have extended our study to p53-mutated human pancreatic cancer Panc-1 cells. According to our present results, knockdown of mutant p53 alone had a marginal effect on GEM-mediated cell death of Panc-1 cells...
October 4, 2016: Oncotarget
Yasushi Sasaki, Miyuki Tamura, Kousuke Takeda, Kazuhiro Ogi, Takafumi Nakagaki, Ryota Koyama, Masashi Idogawa, Hiroyoshi Hiratsuka, Takashi Tokino
The p53 tumor suppressor inhibits cell growth through the activation of both cell cycle arrest and apoptosis, which maintain genome stability and prevent cancer development. Here, we report that intercellular adhesion molecule-2 (ICAM2) is transcriptionally activated by p53. Specifically, ICAM2 is induced by the p53 family and DNA damage in a p53-dependent manner. We identified a p53 binding sequence located within the ICAM2 gene that is responsive to wild-type p53, TAp73, and TAp63. In terms of function, we found that the ectopic expression of ICAM2 inhibited cancer cell migration and invasion...
August 18, 2016: Oncotarget
Yoon Hee Chung, Daejin Kim
The p53 family protein p73 plays an important role in apoptosis induced by chemotherapeutic drugs. Transcriptionally active (TA) p73 (TAp73) substitutes for p53 in the response to stress. XIAP associated factor 1 (XAF1) is a novel predictive and prognostic factor in patients with bladder cancer, but the association between TAp73 and XAF1 expression in bladder cancer cells is poorly understood. Here, we investigated the status of TAp73 and XAF1 in T24 bladder cancer cells to identify molecular mechanisms in casticin‑exposed T24 cells...
August 2016: Oncology Reports
Marco Napoli, Elsa R Flores
Multiciliogenesis is essential for the function of different epithelia, and its failure results in brain defects, respiratory diseases, and infertility. In this issue of Genes & Development, Nemajerova and colleagues (pp. 1300-1312) reveal the p53 family member and p73 isoform TAp73 as a transcription factor dictating the differentiation of multiciliated cells. Their findings provide the long-awaited unifying explanation for the diverse phenotypes of the p73 knockout mice.
June 1, 2016: Genes & Development
M Nakamura, H Sugimoto, T Ogata, K Hiraoka, H Yoda, M Sang, M Sang, Y Zhu, M Yu, O Shimozato, T Ozaki
Pancreatic cancer exhibits the worst prognostic outcome among human cancers. Recently, we have described that depletion of RUNX2 enhances gemcitabine (GEM) sensitivity of p53-deficient pancreatic cancer AsPC-1 cells through the activation of TAp63-mediated cell death pathway. These findings raised a question whether RUNX2 silencing could also improve GEM efficacy on pancreatic cancer cells bearing p53 mutation. In the present study, we have extended our study to p53-mutated pancreatic cancer MiaPaCa-2 cells...
2016: Oncogenesis
Alice Nemajerova, Daniela Kramer, Saul S Siller, Christian Herr, Orr Shomroni, Tonatiuh Pena, Cristina Gallinas Suazo, Katharina Glaser, Merit Wildung, Henrik Steffen, Anusha Sriraman, Fabian Oberle, Magdalena Wienken, Magali Hennion, Ramon Vidal, Bettina Royen, Mihai Alevra, Detlev Schild, Robert Bals, Jürgen Dönitz, Dietmar Riedel, Stefan Bonn, Ken-Ichi Takemaru, Ute M Moll, Muriel Lizé
Motile multiciliated cells (MCCs) have critical roles in respiratory health and disease and are essential for cleaning inhaled pollutants and pathogens from airways. Despite their significance for human disease, the transcriptional control that governs multiciliogenesis remains poorly understood. Here we identify TP73, a p53 homolog, as governing the program for airway multiciliogenesis. Mice with TP73 deficiency suffer from chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance...
June 1, 2016: Genes & Development
H Si, H Lu, X Yang, A Mattox, M Jang, Y Bian, E Sano, H Viadiu, B Yan, C Yau, S Ng, S K Lee, R-A Romano, S Davis, R L Walker, W Xiao, H Sun, L Wei, S Sinha, C C Benz, J M Stuart, P S Meltzer, C Van Waes, Z Chen
The Cancer Genome Atlas (TCGA) network study of 12 cancer types (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform ΔNp63 in squamous cancers. Further, aberrant expression of inflammatory genes and TP53/p63/p73 targets were detected in the PanCancer 12 project, reminiscent of gene programs comodulated by cREL/ΔNp63/TAp73 transcription factors we uncovered in head and neck squamous cell carcinomas (HNSCCs). However, how inflammatory gene signatures and cREL/p63/p73 targets are comodulated genome wide is unclear...
May 2, 2016: Oncogene
Massimiliano Agostini, Margherita Annicchiarico-Petruzzelli, Gerry Melino, Alessandro Rufini
Reactive oxygen species are involved in both physiological and pathological processes including neurodegeneration and cancer. Therefore, cells have developed scavenging mechanisms to maintain redox homeostasis under control. Tumor suppressor genes play a critical role in the regulation of antioxidant genes. Here, we investigated whether the tumor suppressor gene TAp73 is involved in the regulation of metabolic adaptations triggered in response to oxidative stress. H2O2 treatment resulted in numerous biochemical changes in both control and TAp73 knockout (TAp73-/-) mouse embryonic fibroblasts, however the extent of these changes was more pronounced in TAp73-/- cells when compared to control cells...
May 24, 2016: Oncotarget
Mona Salah Al-Din Hamdy, Zainab Ali El-Saadany, Manal Mohamed Makhlouf, Asmaa Ibrahim Salama, Nihal Salah Ibrahim, Alaa Amr Gad
BACKGROUND AND AIMS: The p73 gene has different isoforms with opposing anti- and pro-apoptotic functions. The pro-apoptotic activities are inhibited by overexpression of the dominant ΔNp73 isoform. The aim of this study was to detect the expression of the TAp73 and ΔNp73 isoforms in Egyptian patients with malignant lymphoid neoplasms. Their expression was analyzed by quantitative RT-PCR. PATIENTS AND METHODS: The study included 30 B-NHL patients, 24 T-NHL patients, 16 ALL patients, 18 CLL patients, 22 patients with reactive lymphoid hyperplasia, and 6 healthy control subjects...
April 19, 2016: Tumori
Hesham M Hassan, Michelle L Varney, Nagendra K Chaturvedi, Shantaram S Joshi, Dennis D Weisenburger, Rakesh K Singh, Bhavana J Dave
Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapse and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome. In this report, we investigated whether modulation of p73 isoforms by diclofenac inhibits cell growth, induces apoptosis and/or cell cycle arrest in MCL relative to p53 status. Wild-type p53 [Granta-519 and JVM-2], mutant p53 [Jeko-1 and Mino-1] expressing cells, therapy resistant cell lines, and primary human cells isolated from MCL patients were used...
April 13, 2016: Leukemia & Lymphoma
A K Thakur, J Nigri, S Lac, J Leca, C Bressy, P Berthezene, L Bartholin, P Chan, E Calvo, J L Iovanna, S Vasseur, F Guillaumond, R Tomasini
Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy...
August 2016: Cell Death and Differentiation
Vivien Landré, Alexey Antonov, Richard Knight, Gerry Melino
Glioblastoma Multiforme is one of the most highly metastatic cancers and constitutes 70% of all gliomas. Despite aggressive treatments these tumours have an exceptionally bad prognosis, mainly due to therapy resistance and tumour recurrence. Here we show that the transcription factor p73 confers an invasive phenotype by directly activating expression of POSTN (periostin, HGNC:16953) in glioblastoma cells. Knock down of endogenous p73 reduces invasiveness and chemo-resistance, and promotes differentiation in vitro...
March 15, 2016: Oncotarget
Cong Ren, Jin Zhang, Wensheng Yan, Yanhong Zhang, Xinbin Chen
TAp73, a member of the p53 family tumor suppressors, plays a critical rule in tumor suppression and neuronal development. However, how p73 activity is controlled at the posttranscriptional level is not well understood. Here, we showed that TAp73 activity is regulated by RNA-binding protein PCBP2. Specifically, we found that knockdown or knock-out of PCBP2 reduces, whereas ectopic expression of PCBP2 increases, TAp73 expression. We also showed that PCBP2 is necessary for p73 mRNA stability via the CU-rich elements in p73 3'-UTR...
April 29, 2016: Journal of Biological Chemistry
Kanaga Sabapathy
The role of p73, the homologue of the tumor suppressor p53, in regulating angiogenesis has recently been extensively investigated, resulting in the publication of five articles. Of these, two studies suggested a suppressive role, while the others implied a stimulatory role for the p73 isoforms in regulating angiogenesis. A negative role for TAp73, the full-length form that is often associated with tumor suppression, in blood vessel formation, is consistent with its general attributes and was proposed to be effected indirectly through the degradation of hypoxia-inducible factor 1α (HIF1-α), the master angiogenic regulator...
March 2016: Molecular and Cellular Biology
Michael Fatt, Karolynn Hsu, Ling He, Fredric Wondisford, Freda D Miller, David R Kaplan, Jing Wang
The recruitment of endogenous adult neural stem cells for brain repair is a promising regenerative therapeutic strategy. This strategy involves stimulation of multiple stages of adult neural stem cell development, including proliferation, self-renewal, and differentiation. Currently, there is a lack of a single therapeutic approach that can act on these multiple stages of adult neural stem cell development to enhance neural regeneration. Here we show that metformin, an FDA-approved diabetes drug, promotes proliferation, self-renewal, and differentiation of adult neural precursors (NPCs)...
December 8, 2015: Stem Cell Reports
ZhengBo Hu, ZunYing Xu, XiaoHong Liao, Xiao Yang, Cao Dong, KuaDi Luk, AnMin Jin, Hai Lu
BACKGROUND: TAp73, a member of the p53 tumor suppressor family, is frequently overexpressed in malignant tumors in humans. TAp73 abundance and phosphorylation modification result in variations in transcriptional activity. In a previous study, we found that the antitumor function of TAp73 was reactivated by dephosphorylation in head and neck squamous cell carcinomas. Polo-like kinase 2 (PLK2) displayed a close relationship with the p53 family in affecting the fate of cells. Herein, we investigate the hypothesis that PLK2 phosphorylates TAp73 and inhibits TAp73 function...
2015: OncoTargets and Therapy
Zheng Bo Hu, Xiao Hong Liao, Zun Ying Xu, Xiao Yang, Chao Dong, An Min Jin, Hai Lu
TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53-null and p53-mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo-like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas...
January 2016: Cancer Medicine
Cui-xia Di, Lu Han, Hong Zhang, Shuai Xu, Ai-hong Mao, Chao Sun, Yang Liu, Jing Si, Hong-yan Li, Xin Zhou, Bing Liu, Guo-ying Miao
Diallyl disulfide (DADS), a major organosulfur compound derived from garlic, has various biological properties, including anti-cancer effects. However, the protective mechanism of DADS against radiation-induced mouse testis cell apoptosis has not been elucidated. In this study, the magnitude of radiation effects evoked by carbon ion irradiation was marked by morphology changes, significant rise in apoptotic cells, activation expression of p53, up regulation the ratio of pro-apoptotic Tap73/anti-apoptotic ΔNp73, as well as alterations of crucial mediator of the mitochondrial pathway...
2015: Scientific Reports
Cuixia Di, Chao Sun, Hongyan Li, Jing Si, Hong Zhang, Lu Han, Qiuyue Zhao, Yang Liu, Bin Liu, Guoying Miao, Lu Gan, Yuanyuan Liu
Diallyl disulfide (DADS), extracted from crushed garlic by steam-distillation, has been reported to provide the anticancer activity in several cancer types. However, the effect of DADS on high-LET carbon beams - induced cell death remains unknown. Therefore, we used human cervical cancer cells to elucidate the molecular effects of this diallyl sulfide. Radiotherapy remains the mainstay of treatment, especially in advanced cervical cancer and there is still space to improve the radiosensitivity to reduce radiation dosage...
2015: Cell Cycle
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