RASSF1

This gene encodes a protein similar to the RAS effector proteins.

The RASSF1 gene has eight isoforms, of which RASSF1A and RASSF1C are the most abundantly expressed. These two isoforms are omnipresent in normal cells, where they localize microtubules and regulate cell growth. When expressed normally, RASSF1A causes repression of cyclin A2 and cyclin D1, leading to cell cycle arrest. RASSF1A also plays an important role in microtubule stability by inhibiting histone deacetylase 6 (HDAC6), leading to an increase in acetylated microtubules, which are more stable. RASSF1A binds to microtubule-associated proteins (MAPs) that regulate microtubule stability. RASSF1A also modulates apoptosis. Interaction of RASSF1A with K-Ras activates the apoptotic MST2-LATS1 pathway.{{cite journal | vauthors = Raos D, Ulamec M, Katusic Bojanac A, Bulic-Jakus F, Jezek D, Sincic N | title = Epigenetically inactivated RASSF1A as a tumor biomarker | journal = Bosnian Journal of Basic Medical Sciences | volume = 21 | issue = 4 | pages = 386–397 | date = August 2021 | pmid = 33175673 | pmc = 8292865 | doi = 10.17305/bjbms.2020.5219 }}

RASSF1A is activated by mitogenic stimuli and K-Ras appears to be the major RASSF1A activator upon mitogenic stimulation.

Loss or altered expression of this gene has been associated with the pathogenesis of a variety of cancers, which suggests the tumor suppressor function of this gene. The inactivation of this gene was found to be correlated with the hypermethylation of its CpG-island promoter region. Methylation of CpG-island A is detected in normal tissues and does not affect gene expression. On the other hand, hypermethylation was associated with a loss of RASSF1A expression. The encoded protein was found to interact with DNA repair protein XPA. The protein was also shown to inhibit the accumulation of cyclin D1, and thus induce cell cycle arrest. Seven alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.{{cite web | title = Entrez Gene: RASSF1 Ras association (RalGDS/AF-6) domain family 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11186}} When RASSF1A is epigenetically inactivated, it leads to microtubule instability, suppression of apoptosis, and cell cycle progression, which promotes tumorigenesis.

RASSF1 has been shown to interact with:

• CNKSR1,{{cite journal | vauthors = Rabizadeh S, Xavier RJ, Ishiguro K, Bernabeortiz J, Lopez-Ilasaca M, Khokhlatchev A, Mollahan P, Pfeifer GP, Avruch J, Seed B | display-authors = 6 | title = The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death | journal = The Journal of Biological Chemistry | volume = 279 | issue = 28 | pages = 29247–29254 | date = July 2004 | pmid = 15075335 | doi = 10.1074/jbc.M401699200 | doi-access = free }}
• Death associated protein 6{{cite journal | vauthors = Song MS, Song SJ, Kim SY, Oh HJ, Lim DS | title = The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex | journal = The EMBO Journal | volume = 27 | issue = 13 | pages = 1863–1874 | date = July 2008 | pmid = 18566590 | pmc = 2486425 | doi = 10.1038/emboj.2008.115 }}
• HRAS,{{cite journal | vauthors = Vos MD, Ellis CA, Bell A, Birrer MJ, Clark GJ | title = Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis | journal = The Journal of Biological Chemistry | volume = 275 | issue = 46 | pages = 35669–35672 | date = November 2000 | pmid = 10998413 | doi = 10.1074/jbc.C000463200 | doi-access = free }}
• MAP1B,{{cite journal | vauthors = Dallol A, Agathanggelou A, Fenton SL, Ahmed-Choudhury J, Hesson L, Vos MD, Clark GJ, Downward J, Maher ER, Latif F | display-authors = 6 | title = RASSF1A interacts with microtubule-associated proteins and modulates microtubule dynamics | journal = Cancer Research | volume = 64 | issue = 12 | pages = 4112–4116 | date = June 2004 | pmid = 15205320 | doi = 10.1158/0008-5472.CAN-04-0267 | doi-access = free }}
• MAP1S,{{cite journal | vauthors = Liu L, Vo A, McKeehan WL | title = Specificity of the methylation-suppressed A isoform of candidate tumor suppressor RASSF1 for microtubule hyperstabilization is determined by cell death inducer C19ORF5 | journal = Cancer Research | volume = 65 | issue = 5 | pages = 1830–1838 | date = March 2005 | pmid = 15753381 | doi = 10.1158/0008-5472.CAN-04-3896 | doi-access = free }} and
• RASSF5.{{cite journal | vauthors = Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP, Avruch J | title = The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1 | journal = Oncogene | volume = 21 | issue = 9 | pages = 1381–1390 | date = February 2002 | pmid = 11857081 | doi = 10.1038/sj.onc.1205192 | doi-access = free }}

Cervical cancer is known to be one of the most severe forms of cancer and is frequently associated with human papilloma virus (HPV).{{cite journal | vauthors = Cohen Y, Singer G, Lavie O, Dong SM, Beller U, Sidransky D | title = The RASSF1A tumor suppressor gene is commonly inactivated in adenocarcinoma of the uterine cervix | journal = Clinical Cancer Research | volume = 9 | issue = 8 | pages = 2981–2984 | date = August 2003 | pmid = 12912945 }} A few studies have been done to investigate the relationship between cervical cancers and RASSF1A, an isoform of RASSF1 that has been shown to suppress the proliferation in tumor cells. Through these studies, it was found that RASSF1A is commonly inactivated in adenocarcinomas (ACs) due to hypermethylation of the promoter region. However, this is not observed in squamous cell carcinomas (SCC) of the cervix, though they can be associated with HPV as well. It was found that RASSF1A was silenced in cancer cells when the promoter region was hypermethylated.{{cite journal | vauthors = Li JY, Huang T, Zhang C, Jiang DJ, Hong QX, Ji HH, Ye M, Duan SW | display-authors = 6 | title = Association between RASSF1A Promoter Hypermethylation and Oncogenic HPV Infection Status in Invasive Cervical Cancer: a Meta-analysis | journal = Asian Pacific Journal of Cancer Prevention | volume = 16 | issue = 14 | pages = 5749–5754 | year = 2015 | pmid = 26320446 | doi = 10.7314/apjcp.2015.16.14.5749 | doi-access = free }} It is speculated that cancer subtypes may develop due to the inverse relationship of RASSF1A and HPV. RASSF1A promoter hypermethylation and oncogenic HPV were detected in ACs, but SCCs displayed a high level of HPV DNA and no RASSF1A promoter methylation. Another study used Hela cells to study the potential therapeutic effects of RASSF1A. Hela cells are a line of cells that are derived from cervical cancer cells and are used in scientific research. When Hela cells were generated with RASSF1A expression, the growth of these cells decreased when compared to cells without RASSF1A expression. The rate of apoptosis in those cells had also increased with RASSF1A expression. Through these studies, it was indicated that RASSF1A expression could induce apoptosis and regulate proliferation to suppress tumors, making it a potential therapeutic mechanism for cervical cancers.{{cite journal | vauthors = Feng L, Li J, Yan LD, Tang J | title = RASSF1A suppresses proliferation of cervical cancer cells | journal = Asian Pacific Journal of Cancer Prevention | volume = 15 | issue = 14 | pages = 5917–5920 | year = 2014 | pmid = 25081722 | doi = 10.7314/apjcp.2014.15.14.5917 | doi-access = free }}

Aberrant methylation of RASSF1A has also been found in breast, lung, gastric, liver, and colorectal cancer.

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