Tumor suppressor C-RASSF proteins

Abstract

Human genome has ten genes that are collectedly called Ras association domain family (RASSF). RASSF is composed of two subclasses, C-RASSF and N-RASSF. Both N-RASSF and C-RASSF encode Ras association domain-containing proteins and are frequently suppressed by DNA hypermethylation in human cancers. However, C-RASSF and N-RASSF are quite different. Six C-RASSF proteins (RASSF1-6) are characterized by a C-terminal coiled-coil motif named Salvador/RASSF/Hippo domain, while four N-RASSF proteins (RASSF7-10) lack it. C-RASSF proteins interact with mammalian Ste20-like kinases-the core kinases of the tumor suppressor Hippo pathway-and cross-talk with this pathway. Some of them share the same interacting molecules such as MDM2 and exert the tumor suppressor role in similar manners. Nevertheless, each C-RASSF protein has distinct characters. In this review, we summarize our current knowledge of how C-RASSF proteins play tumor suppressor roles and discuss the similarities and differences among C-RASSF proteins.

UNC119 is a binding partner of tumor suppressor Ras‐association domain family 6 and induces apoptosis and cell cycle arrest by MDM2 and p53

“…The human genome has 10 genes encoding proteins designated as Ras‐association (RA) domain family (RASSF) proteins . RASSF1 to RASSF6 have a RA domain near the C‐terminal region and a coiled‐coiled motif in the C‐terminal region.…”

Ubiquitination‑deubiquitination in the Hippo signaling pathway (Review)

“…RASSF consists of two subclasses, C-RASSF and N-RASSF (223,224). Accumulating evidence indicates that C-RASSF proteins RASSF1-RASSF6 regulate the Hippo pathway through interaction with MST via the SARAH domain, which N-RASSF proteins RASSF7-RASSF10 lack (225). RASSF1A and RASSF1C, which are ubiquitously expressed, are the principal transcripts of the seven alternatively spliced variants of the RASSF1 gene, including isoforms A-G (226).…”

“…Ectopic expression of RASSF1A, by either deletions or promoter hypermethylation of the RASSF1 gene, is associated with various cancer types (226). RASSF1A is considered to be a tumor suppressor due to its critical roles in modulating apoptosis, microtubule stability and cell cycle arrest (225). One of the notable and well-known functions of RASSF1A is that it serves as an upstream regulator of the Hippo pathway.…”

“…Thus, it may be hypothesized that there is another mechanism of interaction between RASSF1A and ITCH that requires investigation. Additionally, RASSF1A may be either a positive or a negative modulator of cell cycle progression by mediating the expression of cyclin, cyclin-dependent kinase, cyclin-dependent kinase inhibitors and other relevant cell-cycle components (225). A previous study determined that Skp2, the F-box protein and substrate-recognition component of SCF Skp2 ligase, targets RASSF1A for ubiquitination and proteolysis at the G 1 /S transition, which requires prior phosphorylation of RASSF1A at Ser203 by cyclin D-Cdk4 (238).…”

The RASSF6 tumor suppressor protein regulates apoptosis and the cell cycle progression via Retinoblastoma protein

“…Ras association domain family (RASSF) 6 is a member of the RASSF proteins (1-3). RASSF6 is epigenetically silenced in acute lymphocytic leukemia, chronic lymphocytic leukemia, neuroblastoma, metastatic melanoma, and gastric cardia adenocarcinoma (4-8).…”