| RASSF1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | RASSF1 , 123F2, NORE2A, RASSF1A, RDA32, REH3P21, Ras association domain family member 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 605082 MGI: 1928386 HomoloGene: 10499 GeneCards: RASSF1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.
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. [5]
RASSF1A is activated by mitogenic stimuli and K-Ras appears to be the major RASSF1A activator upon mitogenic stimulation. [5]
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. [6] 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. [5] 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. [6] When RASSF1A is epigenetically inactivated, it leads to microtubule instability, suppression of apoptosis, and cell cycle progression, which promotes tumorigenesis. [5]
RASSF1 has been shown to interact with:
Cervical cancer is known to be one of the most severe forms of cancer and is frequently associated with human papilloma virus (HPV). [13] 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. [14] Through these studies, it was found that RASSF1A is commonly inactivated in adenocarcinomas (ACs) due to hypermethylation of the promoter region. [13] 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. [15] 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. [14] 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. [14]
Aberrant methylation of RASSF1A has also been found in breast, lung, gastric, liver, and colorectal cancer. [5]
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein. This is explained by splice variants, and an alternative promoter in the DNA sequence.
p14ARF is an alternate reading frame protein product of the CDKN2A locus. p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein). It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively. p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic, and it is polyubiquinated at the N-terminus.
p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.
Runt-related transcription factor 3 is a protein that in humans is encoded by the RUNX3 gene.
Methylated-DNA--protein-cysteine methyltransferase(MGMT), also known as O6-alkylguanine DNA alkyltransferaseAGT, is a protein that in humans is encoded by the MGMT gene. MGMT is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.
CCAAT/enhancer-binding protein alpha is a protein encoded by the CEBPA gene in humans. CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain blood cells. For details on the CCAAT structural motif in gene enhancers and on CCAAT/Enhancer Binding Proteins see the specific page.
Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.
Homeobox protein Hox-A5 is a protein that in humans is encoded by the HOXA5 gene.
Ras association domain-containing protein 5 is a protein that in humans is encoded by the RASSF5 or F5 gene.
Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.
Semaphorin-3B is a protein that in humans is encoded by the SEMA3B gene.
CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Ras association domain-containing protein 2 is a protein that in humans is encoded by the RASSF2 gene.
Large tumor suppressor kinase 2 (LATS2) is an enzyme that in humans is encoded by the LATS2 gene.
Microtubule-associated protein 1S is a protein that in humans is encoded by the MAP1S gene.
Retinoic acid receptor responder protein 1 is a protein that in humans is encoded by the RARRES1 gene.
Yippee-like 3 (Drosophila) is a protein that in humans is encoded by the YPEL3 gene. YPEL3 has growth inhibitory effects in normal and tumor cell lines. One of five family members (YPEL1-5), YPEL3 was named in reference to its Drosophila melanogaster orthologue. Initially discovered in a gene expression profiling assay of p53 activated MCF7 cells, induction of YPEL3 has been shown to trigger permanent growth arrest or cellular senescence in certain human normal and tumor cell types. DNA methylation of a CpG island near the YPEL3 promoter as well as histone acetylation may represent possible epigenetic mechanisms leading to decreased gene expression in human tumors.
GTP-binding protein Di-Ras3 (DIRAS3) also known as aplysia ras homology member I (ARHI) is a protein that in humans is encoded by the DIRAS3 gene.
CpG island hypermethylation is a phenomenon that is important for the regulation of gene expression in cancer cells, as an epigenetic control aberration responsible for gene inactivation. Hypermethylation of CpG islands has been described in almost every type of tumor.
