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)

Cyclin dependent kinases (CDK) associate with cyclins to regulate cell cycle progression and gene transcription by phosphorylating key proteins. The different cyclin-CDK complexes display differences in substrate specificities with substrates binding across a shallow, hydrophobic, substrate-binding pocket known as the cyclin groove. However the mechanism underlying this differential substrate recognition remains largely unknown and cannot be explained merely on the basis of sequence variability. A subset of cyclins, cyclins A2, E1 and B1 despite being structurally and functionally similar, show marked differences in their interactions with recruitment peptides derived from their substrate or inhibitor proteins p27, p21, p57, E2F1, p53, pRb and p107. While these peptides (characterized by a cyclin binding motif of four residues ZRXL where Z and X are cationic residues) inhibit the activity of cyclins A2 and E1, no such inhibition is observed for cyclin B1. Electrostatic potentials of cyclins A2, E1 and B1 show that anionic regions of cyclins A2 and E1 enable them to bind peptides while cationic regions at homologous locations in cyclin B1 abrogate binding. These arise from charged residues that are conserved. Mutations that switch these characters are suggested. Computed energetics of binding confirms this. Deregulation of the enzymatic activity of this class of enzymes is a ubiquitous feature of human neoplasia, but attempts to exploit this therapeutically have been confounded by a lack of understanding of the precise specificity of the different cyclin complexes. Here we begin to clarify this issue by explaining the mechanism by which cyclin B1 escapes regulation by the p21 family of CDKIs.
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PMID:Substrate specificity of cyclins determined by electrostatics. 1789 Sep 1

The specific deletion of Rb gene in epidermis leads to altered proliferation and differentiation, but not to the development of spontaneous tumors. Our previous data have demonstrated the existence of a functional compensation of Rb loss by Rbl1 (p107) in as the phenotypic differences with respect to controls are intensified. However, the possible evolution of this aggravated phenotype, in particular in relationship with tumorigenesis, has not been evaluated due to the premature death of the double deficient mice. We have now investigated whether p107 can also act as a tumor suppressor in pRb-deficient epidermis using different experimental approaches. We found spontaneous tumor development in doubly-deficient skin grafts. Moreover, Rb-deficient keratinocytes are susceptible to Ha-ras-induced transformation, and this susceptibility is enhanced by p107 loss. Further functional analyses, including microarray gene expression profiling, indicated that the loss of p107, in the absence of pRb, produces the reduction of p53-dependent pro-apoptotic signals. Overall, our data demonstrate that p107 behaves as a tumor suppressor in epidermis in the absence of pRb and suggest novel tumor-suppressive roles for p107 in the context of functional p53 and activated Ras.
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PMID:p107 acts as a tumor suppressor in pRb-deficient epidermis. 1793 45

Cervical cancer is the second most common malignancy in women worldwide. Two HPV strains, HPV-16 and 18, occur in the 70% of untreated cancers. Expression of viral oncogenes E6 and E7 disrupt the cell cycle by interfering with p53 and p107(Rb). It is known that HPV infection is necessary but insufficient to cause malignancy. Furthermore, persistence of HPV-16 or 18 in women does not necessarily result in cancer. Persistence indicates the importance of other factors for malignant conversion of high-grade HPV infection. The multi-step cervical carcinogenesis process is amendable to molecular therapeutics such as therapeutic nucleic acids (TNAs). TNA-based therapies for cervical carcinoma include ribozymes, antisense oligonucleotides (AS-ODNs) and small interfering RNAs (siRNAs). In vitro experiments with TNAs successfully inhibited E6/E7 expression and caused induction of apoptosis and/or senescence in cervical carcinoma cells. Early ribozyme and AS-ODN approaches showed promise as therapeutic moieties for cervical cancer. Despite the very high in vitro efficiency of siRNA-based therapies they present the same issues that burdened clinical development of ribozymes and AS-ODNs. These issues include intracellular target accessibility, specificity and delivery. Ribozymes are useful for functional genomic studies including diagnosis. Moreover, AS-ODNs appear better suited for clinical protocols because recent advances in nucleic acid chemistry allow higher cell uptake with very low off-target effects leading to actual AS-ODNs clinical applications. By using combined treatments with multiple targets it will be possible to apply TNAs directly to the cancerous cervix to destroy viral RNA and obliterate the tumor.
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PMID:Molecular approaches to cervical cancer therapy. 1798 3

Functional inactivation of the pRb-dependent pathway is a general feature of human cancer. However, only a reduced spectrum of tumors displays inactivation of the Rb gene. This can be attributed, at least partially, to the possible overlapping functions carried out by the related retinoblastoma family members p107 and p130. We observed that loss of pRb in epidermis, using the Cre/LoxP technology, results in proliferation and differentiation defects. These alterations are partially compensated by the elevation in the levels of p107. Moreover, epidermis lacking pRb and p107, but not pRb alone, develops spontaneous tumors, and double deficient primary keratinocytes are highly susceptible to Ha-ras-induced transformation. Two-stage chemical carcinogenesis experiments in mice lacking pRb in epidermis revealed a reduced susceptibility in papilloma formation and an increase in the malignant conversion. We have now explored whether the loss of one p107 allele, inducing a decrease in the levels of p107 up to normal levels could restore the susceptibility of pRb-deficient skin to two-stage protocol. We observed partial restoration in the incidence, number, and size of tumors. However, there is no increased malignancy despite sustained p53 activation. We also observed a partial reduction in the levels of proapoptotic proteins in benign papillomas. These data confirm our previous suggestions on the role of p107 as a tumor suppressor in epidermis in the absence of pRb.
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PMID:Susceptibility of pRb-deficient epidermis to chemical skin carcinogenesis is dependent on the p107 allele dosage. 1830 Feb 54

Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.
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PMID:Distinct roles for p107 and p130 in Rb-independent cellular senescence. 1841 57

Novel murine models of retinoblastoma based on Rb gene deletion in concert with inactivation of Rb family members have recently been developed. These new Rb knockout models of retinoblastoma provide excellent tools for pre-clinical studies and for the exploration of the genetics of tumorigenesis driven by RB inactivation. This review focuses on the developmental consequences of Rb deletion in the retina and the genetic interactions between Rb and the two other members of the pocket protein family, p107 (Rbl1) and p130 (Rbl2). There is increasing appreciation that homozygous RB mutations are insufficient for human retinoblastoma. Identifying and understanding secondary gene alterations that cooperate with RB inactivation in tumorigenesis may be facilitated by mouse models. Recent investigation of the p53 pathway in retinoblastoma, and evidence of spatial topology to early murine retinoblastoma are also discussed in this review.
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PMID:Insights from mouse models into human retinoblastoma. 1848 54

Certain human papillomaviruses (such as HPV-16 and HPV-18) are associated with specific anogenital cancers, most notably cervical cancer. These viruses encode two oncoproteins, E6 and E7, which are expressed in the HPV positive cancers. E7 functions in cellular transformation, at least in part, through inactivation of pRB, and the other pRB related "pocket proteins" p107 and p130. The major target of the E6 oncoprotein encoded by the genital tract, cancer-associated human papillomaviruses is the p53 tumor suppressor protein. E6 binding to p53 is mediated by a cellular protein, the E6-associated protein (E6AP). In the presence of E6, E6AP catalyses the ubiquitylation and proteolysis of p53. E6AP is an E3 ubiquitin protein ligase and is not normally involved in the regulation of p53 stability in the absence of E6. E6AP is the prototype for the HECT domain family of E3 ubiquitin protein ligases.
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PMID:Warts, cancer and ubiquitylation: lessons from the papillomaviruses. 1852 68

High-risk types of HPV express the oncoproteins, E6 and E7, that can inactivate TP53 and RB1, respectively, and thus take control of both cell cycle and apoptosis. Herein, the mRNA expression profiles of 24 G1/S checkpoint genes were analysed in cancer and squamous intraepithelial lesions (SIL) of the uterine cervix. In total 35 squamous cervical carcinomas, 26 high-grade SIL (HSIL), 33 low-grade SIL (LSIL) tissues, and 28 normal uterine cervix specimens as controls were assessed by RT-PCR. Five genes were found to be upregulated only in tumours, RBL2, E2F2, CDK6, CCNE1 and MYC; eight in tumours and HSILs, E2F1, E2F3, E2F5, CCND1, CDK2, CDKN1B, PCNA and POLA, and five in tumours, HSILs and LSILs, TP53, E2F4, CDKN1A, CDKN2A and DHFR. MDM2 was found to be upregulated in SIL, while RBL1 was found to be downregulated in all three groups of cases. TP73 exhibited lower levels in carcinomas; however, its exon 13-containing isoforms were increased and exon 2-containing isoforms were reduced in both cancer and HSIL. Three genes, RB1, CDK4 and CDKN2D, did not exhibit any significant alteration in gene expression. Hierarchical clustering revealed that this set of G1/S checkpoint genes was able to discriminate the total 122 samples into groups of disease and non-disease with only 8 exceptions (6.6%). Our data suggest that deregulation of G1/S phase transition in cervical carcinogenesis is a progressive process. Certain clusters of genes are activated very early in pre-cancerous SILs while others are activated later, during malignant transformation. The ability of this array of markers to identify disease status suggests that it could be used for diagnostic purposes.
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PMID:Deregulation of the G1/S phase transition in cancer and squamous intraepithelial lesions of the uterine cervix: a case control study. 1881 14

Mouse embryonic fibroblasts (MEFs) deficient for pocket proteins (i.e., pRB/p107-, pRB/p130-, or pRB/p107/p130-deficient MEFs) have lost proper G(1) control and are refractory to Ras(V12)-induced senescence. However, pocket protein-deficient MEFs expressing Ras(V12) were unable to exhibit anchorage-independent growth or to form tumors in nude mice. We show that depending on the level of pocket proteins, loss of adhesion induces G(1) and G(2) arrest, which could be alleviated by overexpression of the TBX2 oncogene. TBX2-induced transformation occurred only in the absence of pocket proteins and could be attributed to downregulation of the p53/p21(CIP1) pathway. Our results show that a balance between the pocket protein and p53 pathways determines the level of transformation of MEFs by regulating cyclin-dependent kinase activities. Since transformation of human fibroblasts also requires ablation of both pathways, our results imply that the mechanisms underlying transformation of human and mouse cells are not as different as previously claimed.
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PMID:Anchorage-independent growth of pocket protein-deficient murine fibroblasts requires bypass of G2 arrest and can be accomplished by expression of TBX2. 1893 68

The study of polyomavirus has benefited immensely from two scientific methodologies, cell culture and in vitro studies on one side and the use of transgenic mice as experimental models on the other. Both approaches allowed us to identify cellular products targeted by the viruses, the consequences of these interactions at the phenotypic and molecular level, and thus the potential roles of the targets within their normal cellular context. In particular, cell culture and in vitro reports suggest a model explaining partially how SV40 large T antigen contributes to oncogenic transformation. In most cases, T antigen induces cell cycle entry by inactivation of the Rb proteins (pRb, p130, and p107), thus activating E2F-dependent transcription and subsequent S-phase entry. Simultaneously, T antigen blocks p53 activity and therefore prevents the ensuing cell-cycle arrest and apoptosis. For the most part, studies of T antigen expression in transgenic mice support this model, but the use of T antigen mutants and their expression in different tissue and cell type settings have expanded our knowledge of the model system and raised important questions regarding tumorigenic mechanisms functioning in vivo.
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PMID:T antigen transgenic mouse models. 1950 50


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