The Ras-association domain family (RASSF) members and their role in human tumourigenesis

Abstract

Ras proteins play a direct causal role in human cancer with activating mutations in Ras occurring in ∼ 30% of tumours. Ras effectors also contribute to cancer, as mutations occur in Ras effectors, notably B-Raf and PI3-K, and drugs blocking elements of these pathways are in clinical development. In 2000, a new Ras effector was identified, RAS-association domain family 1 (RASSF1), and expression of the RASSF1A isoform of this gene is silenced in tumours by methylation of its promoter. Since methylation is reversible and demethylating agents are currently being used in clinical trials, detection of RASSF1A silencing by promoter hypermethylation has potential clinical uses in cancer diagnosis, prognosis and treatment. RASSF1A belongs to a new family of RAS effectors, of which there are currently 8 members (RASSF1–8). RASSF1–6 each contain a variable N-terminal segment followed by a Ras-association (RA) domain of the Ral-GDS/AF6 type, and a specialised coiled-coil structure known as a SARAH domain extending to the C-terminus. RASSF7–8 contain an N-terminal RA domain and a variable C-terminus. Members of the RASSF family are thought to function as tumour suppressors by regulating the cell cycle and apoptosis. This review will summarise our current knowledge of each member of the RASSF family and in particular what role they play in tumourigenesis, with a special focus on RASSF1A, whose promoter methylation is one of the most frequent alterations found in human tumours.

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

“…In flies, the Tapon laboratory reported that dRASSF antagonises Hippo signalling [72], while in human cells RASSF1A activates MST/LATS/ NDR signalling [105][106][107][108]110]. Possibly these differences can be explained by considering other RASSF family members [118,119]. In this context it is noteworthy that Ikeda et al…”

RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7

“…1,2 We co-transfected 293T cells with FLAG-tagged forms of various members of the Ras family, together with myc-tagged RASSF7. We then performed immunoprecipitation assays revealing that RASSF7 was capable of binding tightly to N-Ras (Figure 5b, lane 4) but only weakly to Ki-or R-Ras (lanes 3 and 5).…”

“…[1][2][3] The vertebrate RASSF comprises the classical RASSF members, RASSF1-6, and the more recently identified N-terminal (NT) RASSF members, RASSF7-10. [1][2][3] Epigenetic silencing of most of RASSF genes has been observed at high frequencies in various tumor types.…”

“…[1][2][3] The vertebrate RASSF comprises the classical RASSF members, RASSF1-6, and the more recently identified N-terminal (NT) RASSF members, RASSF7-10. [1][2][3] Epigenetic silencing of most of RASSF genes has been observed at high frequencies in various tumor types. 1,2 In contrast, upregulation of RASSF7 has been noted in pancreatic, endometrial and ovarian cancers, [4][5][6][7][8] although no direct evidence exists indicating that RASSF7 promotes tumorigenesis.…”

Association between RASSF1A Ala133Ser Polymorphism and Cancer Susceptibility: A Meta-Analysis Involving 8,892 Subjects

“…RASSF gene family comprises 10 members, termed RASSF1 to RASSF10. There are seven different RASSF1 isoforms (RASSF1A to RASSF1G) that are generated by differential usage of two promoters and through alternative splicing (van der Weyden and Adams, 2007). Tumor suppressor RASSF1A gene has been reported to play a role in diverse activities including cell cycle regulation, apoptosis and regulating microtubules dynamics as well as maintenance of genomic instability, and thus may serve as a node in the integration of signaling pathways controlling a range of critical cellular functions (Donninger et al,…”