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| | Structure of caveolin-1. Primary structure of caveolin (upper part of the image) with aminoacids colored to illustrate classic domains considered within its molecule. Tertiary structure of caveolin depicted in the lower part of the image shows: 4 alpha-helices, one corresponding to CSD partially embeded in the membrane, 2 alpha-helices corresponding to the transmembrane domain and an alpha helix in C-terminal end with variable length according to different authors. A beta-sheet organized region is also thought to exist in the oligomerisation domain of CAV1. |
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| Description | CAV1 (21-24kDa) is an integral membrane protein, expressing two isoforms (alpha and beta) of different length and distinct potential in caveolae formation. The full length CAV1 (isoform alpha, 178 aminoacids) has a hairpin-like structure spanning the plasmatic membrane, both C- and N-termini facing the cytosol. The beta isoform is 31 aminoacids shorter and is translated from the same mRNA as the longer form, but at divergent translation initiation sites. Both isoforms have two hydrophilic domains at the C- and N-termini, that flank a hydrophobic central domain. Several functional domains were defined. The membrane attachment domains are located at the N- and C-termini and are designated as N-MAD (residues 82-101) and C-MAD (residues 135-150). CAV1 containes palmitoylation sites on Cys 133, 143 and 156, involved in membrane anchorage. The central region (residues 102-134) (TMD) was first suggested to be the transmembrane domain, but, after predicting its beta-sheet rather than alpha-helix conformation, it was suggested that it is involved in hetero-oligomerization of CAV1 with caveolin-2 and in specific interactions with other proteins. The caveolin scaffolding domain (CSD), located at the N-terminus (aminoacids 82-101), is involved in the binding and inhibition of proteins containing a defined caveolin binding motif, such as ωxxxxωxxω or ωxωxxxxω - where ω is an aromatic aminoacid (Trp, Phe or Tyr). The oligomerization domain (aminoacids 61-101) contains CSD and directs the formation of homooligomers (14-16 CAV1 molecules), which interact with cholesterol and signaling molecules.
The structure of CAV1 underlies two separate important functions of the protein: membrane attachment and protein-protein interaction. CAV1 is reported to be involved in various cellular functions, like vesicular transport and regulation of signal transduction in cellular adhesion, growth, and survival. |
| Expression | The table below shows the expression of CAV1 in different organs and tissues. |
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| Localisation | CAV1 is localized in the cytoplasmic side of the peripheral membrane of the cell in caveolae and in the Golgi apparatus membrane.
Membrane protein of caveolae. Potential hairpin-like structure in the membrane. |
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| Function | - Transforming suppressor activity in T cell leukemia.
- Playing a functional role in a novel post-Golgi trafficking pathway.
- Playing a crucial role in the mechanisms that coordinate lipid metabolism with the proliferative response occurring in the liver after cellular injury.
- Being essential for liver regeneration.
- Regulating the trafficking of SLC1A1 on and off the plasma membrane.
- As an important regulator of downstream signaling and membrane targeting of EPHB1.
- CAV1 represents a key switch between tumor suppression and metastases promotion. |
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| Homology | The table above shows the homology of CAV1 with different organisms. |
| Note | Clinical studies accordingly validated high caveolin-1 expression as a negative prognostic factor for the overall and/or disease-free survival in patients with tumors of gastrointestinal (GI) tract (esophagus and oral cavity, pancreas, kidney), prostate, breast, lung, and brain (meningioma). For other entities, including the GI-tract (stomach, colon, liver), bladder, thyroid, brain (glioma) and Ewing's sarcoma, increased caveolin-1 expression compared to matched normal tissue was validated by several independent detection methods (immunohistochemestry, pPCR, cDNAarray), however correlation with clinical outcome is pending (Burgermeister et al., 2008). |
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| Entity | Pancreatic cancer |
| Prognosis | CAV1 expression is increased in pancreatic adenocarcinoma relative to peritumoral tissue. CAV1 expression correlates with tumor size, histological grade, conventional tissue marker for tumor progression and with reduced survival time after tumor resection. Increased CAV1 expression is an independent unfavorable prognostic factor following surgical resection. (Tanase, 2008; Suzuoki et al., 2002). |
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| Entity | Prostate cancer |
| Prognosis | CAV1 expression is increased in metastatic human prostate cancer and that CAV1 cellular protein expression is predictive of recurrence of the disease after radical prostatectomy. Recently, we reported that CAV1 is secreted by androgen-insensitive prostate cancer cells, and we detected, by Western blotting, CAV1 in the high-density lipoprotein(3) fraction of serum specimens from patients with prostate cancer. (Tahir et al., 2003). |
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| Entity | Lung cancer |
| Prognosis | Overexpression of caveolin-1 is significantly correlated with a poor prognosis in patients with pleomorphic carcinoma of the lung (PCL) and that it is a marker for predicting prognosis in PCL (Moon et al., 2005). |
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| Entity | Tyroid papillary carcinoma |
| Prognosis | Studies investigated caveolin-1 expression in thyroid neoplasms by means of immunohistochemistry. Normal follicular cells did not express caveolin-1. In papillary carcinoma, caveolin-1 expression was observed in high incidence, and especially in microcancer. (Ito et al., 2002). |
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| Entity | Brain tumors |
| Prognosis | All studied astrocitomas of any grade (from II to IV) were CAV1 positive, displaying staining patterns and intensity specifically associated to the different tumor grades. In glioblastomas and gliosarcomas, CAV1 staining is extremely intense, typically localized at the cell membrane and recognized a variable percentage of cells, including the majority of spindle cells and palisade-oriented perinecrotic cells. In contrast oligodendrogliomas lacks CAV1 immunoreactivity. A well structured membrane pattern of CAV1 associates with tumor progression, suggesting a neoplastic shift towards a mesenchymal phenotype. (Cassoni et al., 2007). |
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| Entity | Mammary carcinoma |
| Prognosis | No Caveolin-1 expression was observed in epithelial cells of normal breast tissue, benign breast disease and ductal carcinoma in situ. However, Caveolin-1 expression was found in 32 of 109 cases of invasive breast carcinomas (29.4%). Caveolin-1 expression in invasive breast cancer could neither be correlated with survival parameters such as overall or disease-free survival nor with established clinical and pathological markers. (Liedtke et al., 2007). |
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| Caveolin-1 isoforms are encoded by distinct mRNAs. Identification Of mouse caveolin-1 mRNA variants caused by alternative transcription initiation and splicing. |
| Kogo H, Fujimoto T. |
| FEBS Lett. 2000 Jan 14;465(2-3):119-23. |
| PMID 10631317 |
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| Invasion activating caveolin-1 mutation in human scirrhous breast cancers. |
| Hayashi K, Matsuda S, Machida K, Yamamoto T, Fukuda Y, Nimura Y, Hayakawa T, Hamaguchi M. |
| Cancer Res. 2001 Mar 15;61(6):2361-4. |
| PMID 11289096 |
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| Caveolin-1 overexpression is an early event in the progression of papillary carcinoma of the thyroid. |
| Ito Y, Yoshida H, Nakano K, Kobayashi K, Yokozawa T, Hirai K, Matsuzuka F, Matsuura N, Kakudo K, Kuma K, Miyauchi A. |
| Br J Cancer. 2002 Mar 18;86(6):912-6. |
| PMID 11953823 |
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| Src-induced phosphorylation of caveolin-2 on tyrosine 19. Phospho-caveolin-2 (Tyr(P)19) is localized near focal adhesions, remains associated with lipid rafts/caveolae, but no longer forms a high molecular mass hetero-oligomer with caveolin-1. |
| Lee H, Park DS, Wang XB, Scherer PE, Schwartz PE, Lisanti MP. |
| J Biol Chem. 2002 Sep 13;277(37):34556-67. Epub 2002 Jun 28. |
| PMID 12091389 |
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| Impact of caveolin-1 expression on prognosis of pancreatic ductal adenocarcinoma. |
| Suzuoki M, Miyamoto M, Kato K, Hiraoka K, Oshikiri T, Nakakubo Y, Fukunaga A, Shichinohe T, Shinohara T, Itoh T, Kondo S, Katoh H. |
| Br J Cancer. 2002 Nov 4;87(10):1140-4. |
| PMID 12402154 |
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| Development of an immunoassay for serum caveolin-1: a novel biomarker for prostate cancer. |
| Tahir SA, Ren C, Timme TL, Gdor Y, Hoogeveen R, Morrisett JD, Frolov A, Ayala G, Wheeler TM, Thompson TC. |
| Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3653-9. |
| PMID 14506154 |
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| Mutation and aberrant expression of Caveolin-1 in human oral squamous cell carcinomas and oral cancer cell lines. |
| Han SE, Park KH, Lee G, Huh YJ, Min BM. |
| Int J Oncol. 2004 Feb;24(2):435-40. |
| PMID 14719121 |
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| Expression of caveolin-1 in pleomorphic carcinoma of the lung is correlated with a poor prognosis. |
| Moon KC, Lee GK, Yoo SH, Jeon YK, Chung JH, Han J, Chung DH. |
| Anticancer Res. 2005 Nov-Dec;25(6C):4631-7. |
| PMID 16334154 |
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| Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status. |
| Li T, Sotgia F, Vuolo MA, Li M, Yang WC, Pestell RG, Sparano JA, Lisanti MP. |
| Am J Pathol. 2006 Jun;168(6):1998-2013. |
| PMID 16723714 |
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| Caveolin-1 expression is variably displayed in astroglial-derived tumors and absent in oligodendrogliomas: concrete premises for a new reliable diagnostic marker in gliomas. |
| Cassoni P, Senetta R, Castellano I, Ortolan E, Bosco M, Magnani I, Ducati A. |
| Am J Surg Pathol. 2007 May;31(5):760-9. |
| PMID 17460461 |
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| Caveolin-1 expression in benign and malignant lesions of the breast. |
| Liedtke C, Kersting C, Burger H, Kiesel L, Wulfing P. |
| World J Surg Oncol. 2007 Oct 3;5:110. |
| PMID 17915016 |
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| Caveats of caveolin-1 in cancer progression. |
| Burgermeister E, Liscovitch M, Rocken C, Schmid RM, Ebert MP. |
| Cancer Lett. 2008 Sep 18;268(2):187-201. Epub 2008 May 14. |
| PMID 18482795 |
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| Caveolin-1: a tumor-promoting role in human cancer. |
| Shatz M, Liscovitch M. |
| Int J Radiat Biol. 2008 Mar;84(3):177-89. |
| PMID 18300018 |
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| Caveolin-1: a marker for pancreatic cancer diagnosis. |
| Tanase CP. |
| Expert Rev Mol Diagn. 2008 Jul;8(4):395-404. |
| PMID 18598222 |
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