Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD44s (standard form of CD44) is a transmembrane glycoprotein whose external domain displays extracellular matrix adhesion properties by binding both hyaluronic acid (HA) and collagen. The cytoplasmic domain of CD44s interacts with the cytoskeleton by binding directly to ankyrin. It has been shown that post-translational modifications, such as phosphorylation (by protein kinase C), acylation (by acyl-transferase) and GTP-binding enhanced CD44's interaction with cytoskeletal proteins. Most importantly, the interaction between CD44s and the cytoskeletal protein, ankyrin, is required for the modulation of CD44s cell surface expression and its adhesion function. Recently, a number of tumor cells and tissues have been shown to express CD44 variant (CD44v) isoforms. Using RT-PCR and DNA sequence analyses, we have found that unique CD44 splice variant isoforms are expressed in both prostate and breast cancer cell lines and carcinomas. Most importantly intracellular ankyrin is preferentially accumulated underneath the patched/capped structures of CD44 variant isoform in both breast and prostate cancer cells attached to HA-coated plates. We propose that selective expression of CD44v isoforms unique for certain metastatic carcinomas and their interaction with the cytoskeleton may play a pivotal role in regulating tumor cell behavior during tumor development and metastasis.
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PMID:Involvement of CD44 and its variant isoforms in membrane-cytoskeleton interaction, cell adhesion and tumor metastasis. 875 Jan 86

Human erythroid dematin is a cytoskeletal protein capable of bundling actin filaments in vitro. The carboxyl terminal domain of dematin is homologous to the headpiece domain of villin, an actin-binding protein of the brush border cytoskeleton. Here we report the complete structure of the dematin gene located on human chromosome 8p21.1, a region frequently deleted in prostate cancer. The dematin gene is composed of 15 exons spanning approximately 15 kb. We also report two novel isoforms of dematin derived from alternative splicing of the dematin gene in the brain.
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PMID:Alternative splicing and structure of the human erythroid dematin gene. 965 41

Androgens are essential for normal prostate physiology and are intimately associated with the growth and progression of prostate cancer. However, few androgen regulated genes in the prostate have been identified. Using the mRNA differential display technique a 164-bp cDNA fragment was identified as being androgen regulated in the human prostate. Nucleotide sequence analysis of this fragment revealed 84% homology with the gene encoding the cytoskeletal protein talin. Confirmation of the androgen regulation of this gene was carried out using Northern analysis. Primary prostatic stromal cells treated with conditioned medium (CM) from androgen-treated primary prostatic epithelial cells showed an approximate 2-fold reduction in talin mRNA levels compared with stromal cells treated with CM from epithelial cells not exposed to androgens. Expression of talin mRNA in human prostatic tissue was confirmed by in situ hybridisation. The highest levels of expression were present in the epithelial cells, with lower levels of expression in the stroma. Thus, androgen regulation of talin expression may play a role in normal and/or aberrant growth and development of the prostate.
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PMID:Paracrine regulation of talin mRNA expression by androgen in human prostate. 973 53

Dematin is a cytoskeletal protein that bundles actin filaments in a phosphorylation-dependent manner. The primary structure of dematin is organized into an N-terminal core domain of unknown function and a C-terminal domain that is homologous to the "headpiece" domain of villin. We have previously localized the dematin gene on human chromosome 8p21.1, a region distal to the ankyrin locus for hereditary spherocytosis. Radiation hybrid mapping now places dematin between D8S258 and D8S137, two microsatellite markers frequently deleted in prostate cancer. The 8p21.1 region is also deleted in prostate, breast, colon, and bladder cancers, suggesting the presence of a tumor suppressor gene(s). Using laser-capture microdissection technique and fluorescence in situ hybridization (FISH), we demonstrate loss of heterozygosity (LOH) of the dematin gene in a majority of chromosomal region 8p21-linked prostate tumors. One allele of dematin was also deleted in the established prostate adenocarcinoma cell line PC-3, which displays a classic oncogenic phenotype. Overexpression of wild-type dematin in PC-3 cells resulted in the restoration of a more polarized, epithelial-like phenotype. Conversely, the heterologous expression of dominant negative mutants of dematin perturbed normal cell morphology of NIH 3T3 fibroblasts. These results suggest a biological function of dematin in the regulation of cell shape, with implications in the pathobiology of prostate tumorigenesis.
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PMID:Loss of heterozygosity on 8p in prostate cancer implicates a role for dematin in tumor progression. 1056 3

We have identified a novel cytoskeletal protein, EPLIN (Epithelial Protein Lost In Neoplasm), that is preferentially expressed in human epithelial cells. Two EPLIN isoforms, a 600 amino acid EPLIN-alpha and a 759 amino acid EPLIN-beta, are detected in primary epithelial cells of oral mucosa, prostate and mammary glands. The expression of EPLIN-alpha is either down-regulated or lost in the majority of oral cancer cell lines (8/8), prostate cancer cell lines (4/4) and xenograft tumors (3/3), and breast cancer cell lines (5/6). The amino acid sequence of EPLIN is characterized by the presence of a single centrally located LIM domain. Both EPLIN isoforms localize to filamentous actin and suppress cell proliferation when overexpressed. These findings indicate that the loss of EPLIN seen in cancer cells may play a role in cancer progression.
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PMID:EPLIN, epithelial protein lost in neoplasm. 1061 26

The actin cytoskeleton is the key cellular machinery responsible for cellular movement. Changes in the organization and distribution of actin and actin binding protein are necessary for several cellular processes such as focal adhesion formation, cell motility and cell invasion. Here we examined differences in cytoskeletal protein distribution, cell morphometry and cell motility of metastatic and non-metastatic cells. Correlations were found between metastatic potential phenotypic properties such as cell motility, cell spreading and cytoskeletal organization in prostate cancer. As a cell progresses from a normal state to a malignant state, it loses its ability to function normally and also become poorly differentiated. Differentiation therapy is concerned with the redirection of malignant cells toward a terminal, non-dividing state using non-cytotoxic agents. Two well acknowledged differentiation agents, retinoic acid (RA) and diflouromethylomithine (DFMO) were examined for their ability to alter cellular phenotypes associated with metastatic potential in rat prostate cancer cell lines. The results of these studies indicate that there are sub-cellular differences between non-metastatic and highly metastatic cells relative to cytoskeletal organization. We also show that treatment of highly metastatic cells with either RA or DFMO significantly alters cell morphology, cell morphometry and motility to states similar to non-metastatic cells.
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PMID:Cytoskeletal organization and cell motility correlates with metastatic potential and state of differentiation in prostate cancer. 1178 53

The androgen receptor (AR), a nuclear transcription factor, mediates male sexual differentiation, and its excessive action is associated with prostate cancer. We have characterized a negative regulatory domain in the AR hinge region, which interacted with filamin A (FLNa), an actin-binding cytoskeletal protein. FLNa interfered with AR interdomain interactions and competed with the coactivator transcriptional intermediary factor 2 to specifically down-regulate AR function. Although full-length FLNa was predominantly cytoplasmic, a C-terminal 100-kDa fragment of FLNa colocalized with AR to the nucleus. This naturally occurring FLNa fragment repressed AR transactivation and disrupted AR interdomain interactions and transcriptional intermediary factor 2-activated AR function in a manner reminiscent of full-length FLNa, raising the possibility that the inhibitory effects of cytoplasmic FLNa may be transduced through this fragment, which can localize to the nucleus and form part of the pre-initiation complex. This unanticipated role of FLNa adds to the growing evidence for the involvement of cytoskeletal proteins in transcription regulation.
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PMID:Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions. 1268 92

Prostate tumors are initially dependent on androgens for growth, but the majority of patients treated with anti-androgen therapy progress to androgen-independence characterized by resistance to such treatment. This study investigates a novel role for filamin A (FlnA), a 280 kDa cytoskeletal protein (consisting of an actin-binding domain (ABD) followed by 24 sequential repeats), in androgen-independent (AI) growth. Full-length FlnA is cleaved to 170 kDa (ABD+FlnA1-15) and 110 kDa fragments (FlnA16-24); the latter is further cleaved to a 90 kDa fragment (repeats 16-23) capable of nuclear translocation and androgen receptor (AR) binding. Here, we demonstrate that in androgen-dependent LNCaP prostate cancer cells, the cleaved 90 kDa fragment is localized to the nucleus, whereas in its AI subline C4-2, FlnA failed to cleave and remained cytoplasmic. Transfection of FlnA16-24 cDNA in C4-2 cells restored expression and nuclear localization of 90 kDa FlnA. Unlike LNCaP, C4-2 cells proliferate in androgen-reduced medium and in the presence of the AR-antagonist Casodex. They also exhibit increased Akt phosphorylation compared to LNCaP, which may contribute to their AI phenotype. Nuclear expression of 90 kDa FlnA in C4-2 cells decreased Akt phosphorylation, prevented proliferation in androgen-reduced medium and restored Casodex sensitivity. This effect was inhibited by constitutive activation of Akt indicating that FlnA restored Casodex sensitivity in C4-2 cells by decreasing Akt phosphorylation. In addition, FlnA-specific siRNA which depleted FlnA levels, but not control siRNA, induced resistance to Casodex in LNCaP cells. Our results demonstrate that expression of nuclear FlnA is necessary for androgen dependence in these cells.
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PMID:A 90 kDa fragment of filamin A promotes Casodex-induced growth inhibition in Casodex-resistant androgen receptor positive C4-2 prostate cancer cells. 1742 Jul 25

SSeCKS/Gravin/AKAP12 ("SSeCKS") encodes a cytoskeletal protein that regulates G(1) --> S progression by scaffolding cyclins, protein kinase C (PKC) and PKA. SSeCKS is down-regulated in many tumor types including prostate, and when re-expressed in MAT-LyLu (MLL) prostate cancer cells, SSeCKS selectively inhibits metastasis by suppressing neovascularization at distal sites, correlating with its ability to down-regulate proangiogenic genes including Vegfa. However, the forced re-expression of VEGF only rescues partial lung metastasis formation. Here, we show that SSeCKS potently inhibits chemotaxis and Matrigel invasion, motility parameters contributing to metastasis formation. SSeCKS suppressed serum-induced activation of the Raf/MEK/ERK pathway, resulting in down-regulation of matrix metalloproteinase-2 expression. In contrast, SSeCKS had no effect on serum-induced phosphorylation of the Src substrate, Shc, in agreement with our previous data that SSeCKS does not inhibit Src kinase activity in cells. Invasiveness and chemotaxis could be restored by the forced expression of constitutively active MEK1, MEK2, ERK1, or PKCalpha. SSeCKS suppressed phorbol ester-induced ERK1/2 activity only if it encoded its PKC binding domain (amino acids 553-900), suggesting that SSeCKS attenuates ERK activation through a direct scaffolding of conventional and/or novel PKC isozymes. Finally, control of MLL invasiveness by SSeCKS is influenced by the actin cytoskeleton: the ability of SSeCKS to inhibit podosome formation is unaffected by cytochalasin D or jasplakinolide, whereas its ability to inhibit MEK1/2 and ERK1/2 activation is nullified by jasplakinolide. Our findings suggest that SSeCKS suppresses metastatic motility by disengaging activated Src and then inhibiting the PKC-Raf/MEK/ERK pathways controlling matrix metalloproteinase-2 expression and podosome formation.
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PMID:SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase C- Raf/MEK/ERK pathway. 2001 90

The large amounts of microarray data provide us a great opportunity to identify gene expression profiles (GEPs) in different tissues or disease states. Disease-specific biomarker genes likely share GEPs that are distinct in disease samples as compared with normal samples. The similarity of the GEPs may be evaluated by Pearson Correlation Coefficient (PCC) and the distinctness of GEPs may be assessed by Kolmogorov-Smirnov distance (KSD). In this study, we used the PCC and KSD metrics for GEPs to identify disease-specific (cancer-specific) biomarkers. We first analyzed and compared GEPs using microarray datasets for smoking and lung cancer. We found that the number of genes with highly different GEPs between comparing groups in smoking dataset was much larger than that in lung cancer dataset; this observation was further verified when we compared GEPs in smoking dataset with prostate cancer datasets. Moreover, our Gene Ontology analysis revealed that the top ranked biomarker candidate genes for prostate cancer were highly enriched in molecular function categories such as 'cytoskeletal protein binding' and biological process categories such as 'muscle contraction'. Finally, we used two genes, ACTC1 (encoding an actin subunit) and HPN (encoding hepsin), to demonstrate the feasibility of diagnosing and monitoring prostate cancer using the expression intensity histograms of marker genes. In summary, our results suggested that this approach might prove promising and powerful for diagnosing and monitoring the patients who come to the clinic for screening or evaluation of a disease state including cancer.
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PMID:Discovering disease-specific biomarker genes for cancer diagnosis and prognosis. 2044 Dec 32


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