Structure and transforming potential of the human cot oncogene encoding a putative protein kinase.

Abstract

A new transforming gene has been molecularly cloned from hamster SHOK cells transformed with DNA extracted from a human thyroid carcinoma cell line and named the cot (cancer Osaka thyroid) oncogene. cDNA sequencing disclosed that this oncogene codes for a protein with 415 amino acid residues, and computer matching showed 42 to 48% similarity matches with serine protein kinases. Its gene product was identified as a 52-kDa protein by transcription and translation in vitro. Expression of cot cDNA under transcriptional control by a retroviral long terminal repeat induced morphological transformation of NIH 3T3 cells as well as SHOK cells. Protein kinase activity associated with constructed p6(a-Cot was detected by immune complex kinase assay with anti-gag antiserum. The cot oncogene was overexpressed in transformed SHOK cells and found to have a rearranged 3' end in the last coding exon, which probably resulted in a deletion and an altered C' terminus in the transforming protein. This DNA rearrangement appeared to have occurred during transfection of the tumor DNA into hamster SHOK cells and not in the original thyroid tumor.

Overexpression of the Tpl-2/Cot oncogene in human breast cancer

“…Provirus insertion occurs between exon 7 and exon 8 giving rise to a protein with truncated carboxy-terminus. The truncated protein is highly oncogenic when overexpressed in the thymus of transgenic animals inducing thymomas (Ceci et al, 1997) and morphological transformation in SHOK and NIH3T3 cells (Miyoshi et al, 1991). It is expressed in most tissues but at relatively low levels, including ovarian and mammary tissues (Ohara et al, 1995;Erny et al, 1996).…”

“…It is expressed in most tissues but at relatively low levels, including ovarian and mammary tissues (Ohara et al, 1995;Erny et al, 1996). The human Tpl-2 homologue, known as Cot, was initially cloned by transfection of cDNA derived from the thyroid tumour cell line TCO-4 into the hamster cell line SHOK (Miyoshi et al, 1991). In situ hybridization histochemistry in a series of cell lines and tumour tissues revealed that Tpl-2/cot was overexpressed in parotid gland, gastric and colonic gland tumours as well as in the colon adenocarcinoma cell lines SW40 and WiDr (Ohara et al, 1995).…”

Cot protooncoprotein activates the dual specificity kinases MEK-1 and SEK-1 and induces differentiation of PC12 cells

“…The serine/threonine kinase Cot was originally cloned from embryonic SHOK cells transformed with DNA extracted from a human thyroid carcinoma cell line (Miyoshi et al, 1991). The cot gene has su ered a gene rearrangement within the last coding exon of the cot proto-oncogene during this procedure (Miyoshi et al, 1991).…”

“…The cot gene has su ered a gene rearrangement within the last coding exon of the cot proto-oncogene during this procedure (Miyoshi et al, 1991). The ®rst 397 amino acids of the Cot protein are identical to the oncogenic Cot (CotDC), whereas the 70 carboxyterminal amino acids are replaced by 17 completely di erent ones (Aoki et al, 1993).…”

“…Cot and Tpl-2 are highly related at the amino acid level (Miyoshi et al, 1991). Tpl-2 was originally identi®ed as the product of an oncogene involved in the progression of Moloney murine leukemia virusinduced T-cell lymphomas in rats .…”