Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor suppressor p53 is often activated in response to DNA damage or other forms of stress, leading to either cell cycle arrest or apoptosis. Stress-induced kinases phosphorylate p53 thereby enhancing its stability, leading to an increase in transactivation of its target genes. Several different protein kinases phosphorylate p53 on multiple amino acid residues. Here, we report for the first time that Cyclin dependent kinase 9, whose well-known substrate is RNA polymerase II, can also phosphorylate p53. Specifically, Ser33 on the N-terminus and, Ser315 and Ser392 on the C-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated.
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PMID:CDK9 phosphorylates p53 on serine residues 33, 315 and 392. 1655 84

The Period (Per) genes are key circadian rhythm regulators in mammals. Expression of the mouse Per (mPer) genes have diurnal pattern in the suprachiamstic nuclei and in peripheral tissues. Genetic ablation mPER1 and mPER2 function results in a complete loss of circadian rhythm control based on wheel running activity in mice. In addition, these animals also display apparent premature aging and significant increase in neoplastic and hyperplastic phenotypes. When challenged by gamma-radiation, mPer2 deficient mice response by rapid hair graying, are deficient in p53-mediated apoptosis in thymocytes and have robust tumor occurrences. Our studies have demonstrated that the circadian clock function is very important for cell cycle, DNA damage response and tumor suppression in vivo. Temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2 and Gadd45alpha is deregulated in mPer2 mutant mice. In addition, genetic studies have demonstrated that many key regulators of cell cycle and growth control are also important circadian clock regulators confirming the critical role of circadian function in organismal homeostasis. Recently studies of human breast and endometrial cancers revealed that the loss and deregulation of PERIOD proteins is common in the tumor cells.
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PMID:Tumor suppression by the mammalian Period genes. 1659 6

Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis. However, built-in redundancy may limit the effects of highly selective cdk inhibition. Cdk4/6 inhibition has been shown to induce potent G1 arrest in vitro and tumor regression in vivo; cdk2/1 inhibition has the most potent effects during the S and G2 phases and induces E2F transcription factor-dependent cell death. Modulation of cdk2 and cdk1 activities also affects survival checkpoint responses after exposure to DNA-damaging and microtubule-stabilizing agents. The transcriptional cdks phosphorylate the carboxy-terminal domain of RNA polymerase II, facilitating efficient transcriptional initiation and elongation. Inhibition of these cdks primarily affects the accumulation of transcripts with short half-lives, including those encoding antiapoptosis family members, cell cycle regulators, as well as p53 and nuclear factor-kappa B-responsive gene targets. These effects may account for apoptosis induced by cdk9 inhibitors, especially in malignant hematopoietic cells, and may also potentiate cytotoxicity mediated by disruption of a variety of pathways in many transformed cell types. Current work is focusing on overcoming pharmacokinetic barriers that hindered development of flavopiridol, a pan-cdk inhibitor, as well as assessing novel classes of compounds potently targeting groups of cell cycle cdks (cdk4/6 or cdk2/1) with variable effects on the transcriptional cdks 7 and 9. These efforts will establish whether the strategy of cdk inhibition is able to produce therapeutic benefit in the majority of human tumors.
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PMID:Cyclin-dependent kinase pathways as targets for cancer treatment. 1660 19

Arsenic trioxide, an acute promyelocytic leukemia chemotherapeutic, may be an efficacious treatment for other cancers. Understanding the mechanism as well as genetic and molecular characteristics associated with sensitivity to arsenite-induced cell death is key to providing effective chemotherapeutic usage of arsenite. Arsenite sensitivity correlates with deficient p53 pathways in multiple cell lines. The role of p53 in preventing arsenite-induced mitotic arrest-associated apoptosis (MAAA), a form of mitotic catastrophe, was examined in TR9-7 cells, a model cell line with p53 exogenously regulated in a tetracycline-off expression system. Arsenite activated G1 and G2 cell cycle checkpoints independently of p53, but mitotic catastrophe occurred preferentially in p53- cells. Cyclin B/CDC2(CDK1) stabilization and caspase-3 activation persisted in arsenite-treated p53- cells consistent with MAAA/mitotic catastrophe. N-Benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a pan-caspase inhibitor, completely abolished arsenite-induced MAAA/mitotic catastrophe and greatly increased the mitotic index. WEE1 and p21CIP1/WAF1 inhibit cyclin B/CDC2 by CDC2 tyrosine-15 phosphorylation and direct binding, respectively. CDC2-Y15-P was transiently elevated in arsenite-treated p53+ cells but persisted in p53- cells. Arsenite induced p53-S15-P and p21CIP1/WAF1 only in p53+ cells. P21CIP1/WAF1-siRNA-treated p53+ cells were similar to p53- cells in mitotic index and cell cycle protein levels. p53-inducible proteins GADD45alpha and 14-3-3sigma are capable of inhibiting cyclin B/CDC2 but did not play a p53-dependent role in mitotic escape in TR9-7 cells. The data indicate that p53 mediates cyclin B/CDC2 inactivation and mitotic release directly via p21CIP1/WAF1 induction.
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PMID:p53 suppression of arsenite-induced mitotic catastrophe is mediated by p21CIP1/WAF1. 1661 67

Over the past decade important advances have been made in the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). Traditionally, chemotherapy has been incorporated in the treatment of SCCHN either before local treatment as induction, concomitantly with radiation, or following local treatment as adjuvant therapy. A number of randomized trials and meta-analyses have demonstrated that induction chemotherapy (usually based on the combination of cisplatin and 5-d continuous infusion of fluorouracil) followed by local treatment or concomitant chemoradiotherapy (CCRT) each prolongs survival and results in organ preservation in a significant number of patients. Survival rates appear to be higher when CCRT with cisplatin is used. Furthermore, accelerated fractionation radiation regimens have shown improved local control rates in randomized trials. Recently, new therapeutic strategies such as induction chemotherapy followed by CCRT or the incorporation of newer agents such as taxanes are under intense investigation and preliminary results are promising. Advances in molecular biology have led to the elucidation of molecular mechanisms that initiate and maintain the malignant phenotype in SCCHN. The identification of molecular targets has revolutionized our approach to cancer therapy and resulted in the introduction of novel targeted therapies. Cyclin-dependent kinases, the tumor suppressor p53 gene, and epidermal growth factor receptor are some of the molecular targets of such therapies in patients with SCCHN.
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PMID:Advances in the treatment of locally advanced non-nasopharyngeal squamous cell carcinoma of the head and neck region. 1664 25

The progression of mammalian gametogenesis requires a precise balance between cell-cycle activities and elimination of defective gametogenic cells to ensure the perpetuation of species. Both spermatogonia and oogonia are stem cell populations committed to meiosis with the aim of generating haploid gametes for fertilization. At puberty, mitotically dividing spermatogonial cell cohorts maintain the ability of cell renewal and occupy niches in the seminiferous tubule. In contrast, mitotically dividing oogonial cell cohorts produced in the fetal ovary, are exclusively committed to meiosis and produce primordial follicles housing a primary oocyte surrounded by somatic follicular cells. A consistent physiological event during mammalian gametogenesis is the disposal of spermatogenic cells by apoptosis and ovarian follicles by atresia. Cyclin-dependent kinases (Cdks) and their cyclin partners coordinate the activities of the cell cycle. An additional cell-cycle regulatory component is the centrosome. The centrosome harbors regulatory proteins controlling the normal progression of the cell cycle. Changes in individual centrosome proteins can lead to cell-cycle arrest and a decrease in the genomic protective function of p53 that promotes apoptosis. Disruption of cyclin A1, Cdk2, and Cdk4 expression in transgenic mice results in infertility and gonadal atrophy. Cdk-cyclin complexes interact with regulatory proteins, which may fine-tune the activities of the complex. One of the many regulatory proteins is p12, a 115 amino acid growth suppressor polypeptide designated p12(CDK2AP1), partner of Cdk2 and with binding affinity to DNA polymerase alpha/primase. Overexpression of p12 is associated with testicular and ovarian atrophy without affecting fertility. Ectopic expression of p12 was driven by the keratin 14 promoter. Keratin 14 is the pairing partner of keratin 5 and both keratins are expressed in testis. The efficiency of keratin promoters in driving ectopic gonadal gene expression, the association of gonadal atrophy with the ectopic expression of a Cdk2 regulatory protein and the centrosome, as a reservoir of cell-cycle regulatory proteins, open new experimental opportunities to address still lingering questions concerning cell differentiation and division during mammalian gametogenesis.
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PMID:Cell-cycle regulation and mammalian gametogenesis: a lesson from the unexpected. 1670 69

Ultimately aiming at a more individualized therapeutic approach in epidermoid anal cancer, this study explored the prognostic and predictive impact of a set of tumour markers. From a population-based cohort of 276 patients with epidermoid anal cancer, treated according to prospective protocols, 215 pre-treatment biopsies were investigated using immunohistochemistry. The expression of p53, p21, Cyclin A and CD31 was measured semi-quantitatively. The expression rate was classified as high when immunostaining was seen in > 5% of the tumour cells for p53 and p21, > 20% in Cyclin A and, above median vessel count for CD31. Marker expression was correlated to survival and treatment response. A high Cyclin A expression correlated significantly with improved overall (77% vs 59%, p = 0.005) and tumour-specific (81% vs 64%, p = 0.009) survival at 5 years. Also, the locoregional failure rate was significantly lower in patients with a high Cyclin A expression (12% vs 24%, p < 0.05). In a multivariate Cox analysis Cyclin A was an independent prognostic factor. A low p21 expression correlated with a reduced rate of locoregional failure (14% vs 27%, p < 0.05) but no impact on survival was found. For p53 and CD31 no significant correlations were obtained. Cyclin A may be an indicator of radiosensitivity and a valuable prognostic marker in epidermoid anal cancer.
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PMID:Prognostic significance of Cyclin A in epidermoid anal cancer. 1686 41

The exact mechanism behind the effect of hypoxia-inducible factor-1alpha (HIF-1alpha) on the proliferation and/or apoptosis of carcinoma cells is still a matter of debate. We treated a human gastric carcinoma cell line, MKN-1 (mutant P53), with 500 microM CoCl(2). A dual-phase pattern of HIF-1alpha expression with an increase until 4 h followed by a decrease until 36 h was observed. Immunocytochemistry showed that nuclear translocation was maximal at 4 h of treatment, while trypan blue staining showed a dual-phase pattern. Instead of G1/S arrest, FACS showed an increase in the pre-G1 fraction and G(2)/M arrest that correlated with Cyclin-B1, SKP-2 and P27 expression. Starting at 6 h, the apoptotic index increased in a time-dependent manner, in correlation with the expression of HIF-1alpha, Bcl-2, Bcl-xL, Bax and cleaved-Caspase-9. Phosphorylation of Akt was inhibited by CoCl(2) treatment and LY294002 treatment inhibited HIF-1alpha expression in a dose-dependent manner. These results suggested that the alteration of CoCl(2)-induced HIF-1alpha expression correlated with proliferation and apoptosis in MKN-1 cells. A possible role for the PI3K/Akt pathway was indicated in this model of hypoxia.
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PMID:CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway. 1686 70

The objective of this study was to determine the correlation of the expression of cyclin D1 and E1 with the expression of commonly altered cell cycle regulators and bladder cancer presence, staging, and clinical outcomes. We performed immunohistochemical staining for cyclin D1, cyclin E1, p53, p21, p27, and retinoblastoma protein (pRB) on serial cuts from normal urothelium from 9 controls, radical cystectomy specimens from 226 consecutive patients with advanced transitional cell carcinoma, and lymph nodes with metastasis from 50 of the 226 cystectomy patients. Cyclin D1 and E1 immunoreactivity were considered low when samples demonstrated less than 10% and 30% nuclear reactivity, respectively. Normal bladder urothelium from all 9 control patients showed uniformly intense expression of cyclin D1 and E1. Cyclin D1 expression was low in 99 (43.8%) of 226 cystectomy specimens and 25 (50.0%) of 50 metastatic lymph node specimens. Cyclin D1 immunoreactivity was not associated with any pathologic characteristics or clinical outcomes. Cyclin E1 expression was low in 125 (55.3%) of 226 cystectomy specimens and 22 (44.0%) of 50 metastatic lymph node specimens. Low cyclin E1 expression was significantly associated with advanced pathologic stage, lymphovascular invasion, and lymph node metastases. In multivariate analyses, low cyclin E1 expression was significantly associated with bladder cancer-specific mortality (P = .048), but not disease recurrence (P = .056). Low cyclin E1 expression was significantly associated with altered expression of pRB, p27, and cyclin D1. Low cyclin D1 expression was significantly associated with altered expression of pRB, p21, and cyclin E1. Cyclin E1 expression stratifies patients with bladder transitional cell carcinoma into those with more "indolent" behavior and those with features of biologically and clinically aggressive disease.
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PMID:Correlation of cyclin D1 and E1 expression with bladder cancer presence, invasion, progression, and metastasis. 1694 11

The naturally-occurring compound, n-butylidenephthalide (BP), which is isolated from the chloroform extract of Angelica sinensis (AS-C), has been investigated with respect to the treatment of angina. In this study, we have examined the anti-tumor effects of n-butylidenephthalide on glioblastoma multiforme (GBM) brain tumors both in vitro and in vivo. In vitro, GBM cells were treated with BP, and the effects of proliferation, cell cycle and apoptosis were determined. In vivo, DBTRG-05MG, the human GBM tumor, and RG2, the rat GBM tumor, were injected subcutaneously or intracerebrally with BP. The effects on tumor growth were determined by tumor volumes, magnetic resonance imaging and survival rate. Here, we report on the potency of BP in suppressing growth of malignant brain tumor cells without simultaneous fibroblast cytotocixity. BP up-regulated the expression of Cyclin Kinase Inhibitor (CKI), including p21 and p27, to decrease phosphorylation of Rb proteins, and down-regulated the cell-cycle regulators, resulting in cell arrest at the G(0)/G(1) phase for DBTRG-05MG and RG2 cells, respectively. The apoptosis-associated proteins were dramatically increased and activated by BP in DBTRG-05MG cells and RG2 cells, but RG2 cells did not express p53 protein. In vitro results showed that BP triggered both p53-dependent and independent pathways for apoptosis. In vivo, BP not only suppressed growth of subcutaneous rat and human brain tumors but also, reduced the volume of GBM tumors in situ, significantly prolonging survival rate. These in vitro and in vivo anti-cancer effects indicate that BP could serve as a new anti-brain tumor drug.
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PMID:The natural compound n-butylidenephthalide derived from Angelica sinensis inhibits malignant brain tumor growth in vitro and in vivo. 1698 98


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