Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3

Abstract

Allelic loss at the short arm of chromosome 3 is one of the most common and earliest events in the pathogenesis of lung cancer, and is observed in more than 90% of small-cell lung cancers (SCLCs) and in 50-80% of non-small-cell lung cancers (NSCLCs). Frequent and early loss of heterozygosity and the presence of homozygous deletions suggested a critical role of the region 3p21.3 in tumorigenesis and a region of common homozygous deletion in 3p21.3 was narrowed to 120 kb (ref. 5). Several putative tumour-suppressor genes located at 3p21 have been characterized, but none of these genes appear to be altered in lung cancer. Here we describe the cloning and characterization of a human RAS effector homologue (RASSF1) located in the 120-kb region of minimal homozygous deletion. We identified three transcripts, A, B and C, derived from alternative splicing and promoter usage. The major transcripts A and C were expressed in all normal tissues. Transcript A was missing in all SCLC cell lines analysed and in several other cancer cell lines. Loss of expression was correlated with methylation of the CpG-island promoter sequence of RASSF1A. The promoter was highly methylated in 24 of 60 (40%) primary lung tumours, and 4 of 41 tumours analysed carried missense mutations. Re-expression of transcript A in lung carcinoma cells reduced colony formation, suppressed anchorage-independent growth and inhibited tumour formation in nude mice. These characteristics indicate a potential role for RASSF1A as a lung tumour suppressor gene.

Frequent chromosome 9p losses in histologically normal nasopharyngeal epithelia from southern Chinese

“…The tumor suppressor genes p16 and RASSF1A are located in the regions 9p21 and 3p21.3, respectively. 9,11 Studies have demonstrated high frequencies of inactivation of these genes in nasopharyngeal carcinoma. 9,10,12 Our findings reflect the importance of alterations in these chromosomal regions and inactivation of the target genes in NPC genesis.…”

Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer

“…31,32 NORE1 and RASSF1 are two members of the RASSF family known to have putative RAS-binding domains and mediate RAS-induced apoptotic signals. [33][34][35] Further studies demonstrated that these two proteins are binding partners of Mst1 and their complex formation with Mst1 is critical to the mechanism of RAS-induced apoptosis (Figure 1). 36,37 Loss of Mst1 expression will change the balance of RAS-induced contradictory signals in favor of anti-apoptotic ones and provide a further explanation for the association of clinico-pathological outcomes and Mst1 expression in MMR proficient colorectal cancers.…”

Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1–S transition

“…RASSF1A is a tumor suppressor gene on chromosome 3p21 that is inactivated in many types of carcinoma (Dammann et al, 2000). Moreover, knockout mice defective for RASSF1A are prone to tumor development van der Weyden et al, 2005), further confirming that RASSF1A functions as a tumor suppressor.…”

“…Given that RASSF1A has a tumor suppressor function by inhibiting cell proliferation and survival (Dammann et al, 2000;Shivakumar et al, 2002;Song et al, 2004;Baksh et al, 2005), we thus examined whether Skp2 inhibits the tumor suppression function of RASSF1A. Overexpression of wild-type and S203A mutant forms of RASSF1A resulted in a significant loss of viability in U2OS cells (Figures 6a and b).…”