The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines

Abstract

Alterations of 19q13 are frequently observed in glial neoplasms, suggesting that this region harbors at least one gene involved in gliomagenesis. Following our previous studies on structural 19q chromosome rearrangements in gliomas, we have undertaken a detailed FISH analysis of the breakpoints and identified a 19q13.2 intrachromosomal amplification of the MAP/microtubule affinityregulating kinase 4 (MARK4) gene in three primary glioblastoma cell lines. Recent data suggest that this gene is involved in the Wnt-signaling pathway. We observed that the expression of the alternatively spliced MARK4L isoform is upregulated in both fresh and cultured gliomas and overexpressed in all of the above three glioblastoma cell lines. Interestingly, we also found that MARK4L expression is restricted to undifferentiated neural progenitor cells or proliferating glial precursor cells, whereas its expression is downregulated during glial differentiation. Perturbation of expression using antisense oligonucleotides against MARK4 in glioblastoma cell lines, consistently induced a decreased proliferation of tumor cells. Taken together, these data show that MARK4, which is normally expressed in neural progenitors, is reexpressed in gliomas and may become a key target of intrachromosomal amplification upon 19q rearrangements.

miR‐515‐5p controls cancer cell migration throughMARK4 regulation

“…Moreover, MARK4 was clearly up‐regulated during lung tumorigenesis and further increased in metastatic lesions in over 40% of cases (Fig 5C–F). MARK4 has previously been shown to be up‐regulated in glioma and hepatocellular carcinomas 1, 2 and associated with Wnt‐induced tumorigenesis in the prostate 21. Nevertheless, this is the first report of its overexpression during lung tumorigenesis and of its particular association with the metastatic process.…”

“…To date, MARK4 expression has been found to be increased in hepatocellular carcinomas and gliomas, suggesting a role for MARK4 in cancer development 1, 2. Using a tandem affinity purification approach, MARK4 was found to interact with a number of proteins linked to the regulation of cell motility, namely 14‐3‐3 proteins, ARHGEF2 (GEF‐H1)—a microtubule‐associated exchange factor for Rho GTPases and phosphatase 2A (PP2A), and was previously shown to dephosphorylate TAU and other MAPs controlling their microtubule‐binding affinity 3, 4.…”

Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines

“…DNA copy number changes detected by the full chromosome 19 coverage subarray Motivated by the frequent involvement of chromosome 19q in gliomas (von Deimling et al, 1992(von Deimling et al, , 1994Ohgaki et al, 1995;Ritland et al, 1995;Smith et al, 1999;Schmidt et al, 2002) and our recent data on the duplication of MARK4 in three GBM cell lines (Beghini et al, 2003), we pursued a high-resolution characterization of chromosome 19 in our cell lines through the use of full genomic coverage aCGH for this particular chromosome.…”

“…We postulated a possible role for the novel serine threonine kinase gene MARK4, which maps at the centromeric boundary of the 19q13.3 LOH region, and which is overexpressed and duplicated in three GBM cell lines (Beghini et al, 2003).…”

Overexpression of SERTAD3, a putative oncogene located within the 19q13 amplicon, induces E2F activity and promotes tumor growth

“…In particular, amplification of chromosome 19q13 has been linked to different types of cancers including pancreatic carcinoma (Miwa et al, 1996;Curtis et al, 1998;Hoglund et al, 1998), ovarian carcinoma (Thompson et al, 1996;Bicher et al, 1997;Wang et al, 1999), breast cancer (Muleris et al, 1995) and other cancers (Marchio et al, 1997;Petersen et al, 1997;Beghini et al, 2003), supporting that genes included in this amplicon can participate in tumor formation.…”