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

Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent. Although inactivation of some tumor suppressor genes such as p53 and p16INK4Ahas been identified, no known oncogene is commonly activated in hepatocellular carcinomas. Here we have isolated genes overexpressed in hepatocellular carcinomas by cDNA subtractive hybridization, and identified an oncoprotein consisting of six ankyrin repeats (gankyrin). The expression of gankyrin was increased in all 34 hepatocellular carcinomas studied. Gankyrin induced anchorage-independent growth and tumorigenicity in NIH/3T3 cells. Gankyrin bound to the product of the retinoblastoma gene (RB1), increasing its phosphorylation and releasing the activity of the transcription factor E2F-1. Gankyrin accelerated the degradation of RB1 in vitro and in vivo, and was identical to or interacted with a subunit of the 26S proteasome. These results demonstrate the importance of ubiquitin-proteasome pathway in the regulation of cell growth and oncogenic transformation, and indicate that gankyrin overexpression contributes to hepatocarcinogenesis by destabilizing RB1.
 ...
PMID:Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. 1061 32

Recently it has been shown that the VHL tumor suppressor targets the hypoxia-inducible transcription factor (HIF-1) for ubiquitin-dependent degradation by the proteasome. Past mysteries of the p53 tumor suppressor help to solve the present puzzles of the VHL tumor suppressor. Thus, Mdm-2 targets the p53 tumor suppressor for ubiquitin-dependent degradation by the proteasome, but, in addition, the p53 transcription factor induces Mdm-2, thus, establishing a feedback loop. Hypoxia or DNA damage by abrogating binding of HIF-1 with VHL and p53 with Mdm-2, respectively, leads to stabilization and accumulation transcriptionally active HIF-1 and p53. More detailed analysis depicts the VHL/HIF-1 pair as the p53/mdm-2 pair that is turned upside down, suggesting that VHL may be a HIF-1-inducible gene of the feedback loop. The extended model proposes that an oncoprotein and a tumor suppressor due to transactivation coupled with feedback protein degradation might form functional pairs (Rb/E7, E2F/Rb, E2F/Mdm-2, catenin/APC, p27, cyclin D1, Rb/gankyrin), thus, predicting missing links.
 ...
PMID:Do VHL and HIF-1 mirror p53 and Mdm-2? Degradation-transactivation loops of oncoproteins and tumor suppressors. 1131 69

Gankyrin is a 25-kDa hepatocellular carcinoma-associated protein that mediates protein-protein interactions in cell cycle control and protein degradation. It has been reported to form complexes with cyclin-dependent kinase 4, retinoblastoma protein, the S6b ATPase subunit of the 19 S regulator of the 26 S proteasome, and Mdm2, an E3 ubiquitin ligase involved in p53 degradation. It is the first protein described to bind both to the 26 S proteasome and to proteins in other complexes containing cyclin-dependent kinase(s) and p53 ubiquitylating activities, thus providing a mechanism for delivering cell cycle regulating machinery and ubiquitylated substrates to the proteasome for degradation. Gankyrin contains a 33-residue motif known as the ankyrin repeat that occurs five and a half to six times in the sequence. As a step toward understanding gankyrin interactions with its protein partners we have determined its three-dimensional crystal structure to 2.0-A resolution. It reveals that the entire 226-residue gankyrin polypeptide folds into seven ankyrin repeat elements. The ankyrin repeats, consisting of an antiparallel beta-hairpin followed by a perpendicularly oriented helix-loop-helix, pack side-by-side, creating an extended curved structure with a groove running across the long concave surface. Comparison with the structures of other ankyrin repeat proteins suggests that interactions with partner proteins are mediated by residues situated on this concave surface.
 ...
PMID:The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53. 1457 99

Gankyrin, a recently discovered oncoprotein, is a promising target for drug therapy because it is overexpressed in most hepatocellular carcinomas. Since gankyrin interacts with MAGE-A4, we made several MAGE-A4 mutants and assessed their effects on cell growth. We found that the C-terminal 107 amino acids of MAGE-A4 (MAGE-A4DeltaN1) induced p53-dependent and p53-independent apoptosis. MAGE-A4DeltaN1 increased the p53 protein level, but decreased the p21(Cip1) transcript and protein levels. During apoptosis Bcl-xL was down-regulated and mitochondrial integrity was disrupted. A yeast two-hybrid screen identified Miz-1 as a MAGE-A4DeltaN1-binding protein. MAGE-A4DeltaN1 was recruited through association with Miz-1 to the p21(Cip1) promoter and down-regulated transcription of p21(Cip1). In 293T cells and U-2 OS cells, full-length MAGE-A4 was processed to generate a C-terminal fragment of 104 amino acids with activities similar to MAGE-A4DeltaN1. Processing was inhibited with a broad range caspase inhibitor Z-VAD-FMK, but not by site-directed mutagenesis of aspartic acids in MAGE-A4, suggesting an indirect involvement of caspase(s) in the processing. The amount of the processed form was increased by exposure of cells to adriamycin. Transduction with a HIV Tat-MAGE-A4DeltaN1 fusion protein suppressed anchorage-independent growth of gankyrin-overexpressing cells in vitro and in vivo. These results demonstrate that the C-terminal fragment of MAGE-A4 induces apoptosis at least partly by binding to Miz-1, and that the fragment may be exploited as an anticancer agent. Furthermore, the finding that a C-terminal fragment with pro-apoptotic activity is generated from full-length MAGE-A4 after genotoxic stress in human cells suggests a novel function for MAGE-A4.
 ...
PMID:A cleaved form of MAGE-A4 binds to Miz-1 and induces apoptosis in human cells. 1473 98

The RB and p53 tumor suppressors lie at the heart of cancer biology, and inactivation of both pathways is seemingly essential for tumor development. Previous studies identified gankyrin as a component of the 26S proteasome that is consistently overexpressed in liver cancer and promotes cell transformation by binding RB. In the current issue of Cancer Cell, Fujita and colleagues (Higashitsuji et al., 2005) show that gankyrin also binds MDM2 and facilitates its destruction of p53. These important findings implicate gankyrin as a dual-purpose negative regulator of RB and p53, thereby identifying gankyrin as a rational cancer therapeutic target.
 ...
PMID:Gankyrin: an intriguing name for a novel regulator of p53 and RB. 1602 92

Gankyrin is an ankyrin repeat oncoprotein commonly overexpressed in hepatocellular carcinomas. Gankyrin interacts with the S6 proteasomal ATPase and accelerates the degradation of the tumor suppressor Rb. We show here that gankyrin has an antiapoptotic activity in cells exposed to DNA damaging agents. Downregulation of gankyrin induces apoptosis in cells with wild-type p53. In vitro and in vivo experiments revealed that gankyrin binds to Mdm2, facilitating p53-Mdm2 binding, and increases ubiquitylation and degradation of p53. Gankyrin also enhances Mdm2 autoubiquitylation in the absence of p53. Downregulation of gankyrin reduced amounts of Mdm2 and p53 associated with the 26S proteasome. Thus, gankyrin is a cofactor that increases the activities of Mdm2 on p53 and probably targets polyubiquitylated p53 into the 26S proteasome.
 ...
PMID:The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. 1602

Ubiquitin-dependent proteolysis mediates selective destruction of various cell cycle regulators, transcription factors and tumor suppressors. Gankyrin, a seven ankyrin-repeat protein, was originally identified as an oncoprotein commonly overexpressed in hepatocellular carcinomas and independently as a protein associated with the 19S regulatory complex of the 26S proteasome. Gankyrin also binds to CDK4 and the tumor suppressor RB, and accelerates phosphorylation and proteasomal degradation of RB. Recently, we have shown that gankyrin has an anti-apoptotic activity in cells exposed to DNA-damaging agents. Gankyrin binds to MDM2, a major E3 ubiquitin ligase for p53, and increases ubiquitylation and degradation of p53. Gankyrin increases activities of CDK4 and MDM2, and facilitates targeting of polyubiquitylated proteins to the 26S proteasome. Furthermore, inhibition of gankyrin induces apoptosis in cancer cells. Therefore, gankyrin is a promising target for potential anticancer therapeutic agents.
 ...
PMID:The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation. 1617 71

Apoptosis is an essential part of normal embryonic development in vertebrates, and it is involved in sculpturing organs and controlling cell populations. In previous studies, we identified two novel proteins, zfBLP1 and zfMcl-1a, which are similar to those of the Bcl-2 family as a group of evolutionarily conserved proteins that regulate cellular anti-apoptosis. To evaluate the effect of dysregulated hepatocyte apoptosis during zebrafish hepatogenesis, we demonstrate the transgenic overexpression of either zfBLP1 or zfMcl-1a in zebrafish larval liver. Results showed that 18%-43% of larvae overexpressed zfBLP1 and that 16%-37% of larvae overexpressed zfMc1-1a in the liver leading to liver hyperplasia in 5-day postfertilization (dpf) zebrafish larvae. Histologically, zebrafish larvae exhibiting liver hyperplasia displayed a normal type of hepatocyte and the same cell numbers in their two liver buds compared with only one liver bud of wild-type larvae. Of interest, the expression of cyclin genes (A2, B, D1, and E), hepatocyte nuclear factor genes (HNF-1alpha, beta, -3beta, and 4alpha), and oncogenic markers (P53, c-myc, beta-catenin, N-ras, and gankyrin) were up-regulated, while the expression of C/EBP-alpha was down-regulated in a zfMcl-1a-mediated anti-apoptotic process of the liver. Increased cell death and proliferation was found in both hepatic cells of zebrafish larvae overexpressing either zfBLP1 or zfMcl-1a. However, those zebrafish larvae with liver hyperplasia only lived approximately 10 days. (This finding may have been due to liver abnormalities that led to failure of liver function.) In conclusion, transgenic overexpression of zfBLP1 or zfMcl-1a in zebrafish larvae interrupts regulation of the homeostatic balance between cell proliferation and programmed cell death during hepatogenesis and leads to liver hyperplasia.
 ...
PMID:Imbalance in liver homeostasis leading to hyperplasia by overexpressing either one of the Bcl-2-related genes, zfBLP1 and zfMcl-1a. 1627 21

Inactivation of retinoblastoma protein (Rb) plays a key role in human tumorigenesis. Although the regulation of Rb by phosphorylation has been extensively studied, the regulation of proteasome-mediated Rb protein degradation is largely unknown. Viral oncoprotein E7, Epstein-Barr virus nuclear antigen 3C (EBNA3C), human cytomegalovirus pp71 and cellular oncoprotein gankyrin all contain the L-x-C-x-E Rb-binding motif and target Rb protein for degradation in either ubiquitin-dependent or ubiquitin-independent proteasome pathways. The molecular mechanisms, however, remain elusive. The MDM2 oncoprotein is overexpressed in a variety of human cancers. MDM2 functions as an ubiquitin E3 ligase and induces p53 protein degradation through ubiquitination-proteasome pathway. Both MDM2 central acidic domain and the C-terminal RING domain are critical for p53 degradation. MDM2 also interacts with Rb through its central acidic domain and inhibits Rb function in part by blocking Rb-E2F-DNA complex formation. Recently, we showed that MDM2 binds to C8 subunit of 20S proteasome and promotes Rb-C8 interaction, leading to a proteasome-dependent ubiquitin-independent degradation of Rb. Knockdown of MDM2 results in accumulation of hypophosphorylated Rb and inhibition of DNA synthesis. Taken together, we suggest that targeting Rb protein for degradation by proteasomes may represent a common neoplastic strategy during human cancer development.
 ...
PMID:Targeting retinoblastoma protein for degradation by proteasomes. 1655 88

Gankyrin is a new oncoprotein with potent cell cycle and apoptotic properties that is overexpressed early in hepatocarcinogenesis and in hepatocellular carcinomas. Gankyrin regulates the phosphorylation of the retinoblastoma protein (pRb) by CDK4 and enhances the ubiquitylation of p53 by the RING ubiquitin ligase MDM2. Purified preparations of the 26S proteasome contain gankyrin, which specifically interacts with the S6b (Rpt3) ATPase of the 19S regulator. In conclusion, gankyrin is a small versatile cell cycle regulator that illustrates the essential interplay between the ubiquitin proteasome system and gene expression in the cell. Here, we discuss the activities of gankyrin and present a model for its function in the regulation of pRb and p53.
 ...
PMID:Gankyrin: a new oncoprotein and regulator of pRb and p53. 1658 Dec 49


1 2 3 4 Next >>