Proto-Oncogenes Their Role in Cancer - Article Example

 Proto-Oncogenes Their Role in Cancer Abstract Proto-oncogenes are activated homologues of mammalian genes, which are activated by various mechanisms to cause cancer. They are classified into various types, of which the ras family has been detected more frequently and in more human tumor types like colon carcinomas, pancreatic carcinomas, lung adenocarcinomas, cholangiocarcinomas, certain types of thyroid tumors, endometrial adenocarcinomas, etc. The non-ras proto-oncogenes causing cancer include : N-myc, e-myc, C-myc, hst-1, HER2/neu, K-ras, L-myc, N-myc , C-myc, and int-2/hst-1 genes. The amplification of proto-oncogenes and possibly gene overexpression in the absence of gene amplification are important events in the development of many human tumors. Proto-oncogenes Specific genes of chicken and rodent retroviruses were first noted to transform normal mammalian cells in culture. These cancer-causing genes (oncogenes) proved to be activated homologues of mammalian genes (proto-oncogenes), which were stolen from the host cell during viral evolution. Primary human cancers harbor similar activated alleles of proto-oncogenes (Haber, 2006) Some of the mechanisms by which proto-oncogenes are activated in human cancers include: point mutations, gene amplification, and chromosomal translocations. These mutations are known as gain-of-function mutations because “they result in novel or altered functional properties for the encoded protein and are genetically dominant over the second normal allele”(Haber, 2006) Proto-oncogenes can be classified based either on their normal function within cells or upon sequence homology to other known proteins (National Science Teachers Association. 2001). “Proto-oncogenes that were originally identified as resident in transforming retroviruses are designated as c- indicative of the cellular origin as opposed to v- to signify original identification in retroviruses” (National Science Teachers Association. 2001). The classification listed below includes only those genes that have been highly characterized (National Science Teachers Association. 2001). I. Growth Factors a. The c-Sis gene encodes the PDGF B chain. b. The int-2 gene encodes an FGF-related growth factor. c. The KGF (or Hst) gene encodes an FGF-related growth factor and was identified in gastric carcinoma and Kaposi's sarcoma cells. II. Receptor Tyrosine Kinases a. The c-Fms gene encodes the colony stimulating factor-1 (CSF-1). b. The Flg gene encodes a form of the FGF receptor. c. The Neu gene identified as an EGF receptor-related gene in neuroblastoma. d. The Trk genes encodes the NGF receptor-like proteins. The first Trk gene was found in a pancreatic cancer. Subsequently, two additional Trk-related genes were identified (TrkA, TrkB and TrkC). e. The Met gene encodes the hepatocyte growth factor (HGF)/scatter factor (SF) receptor. f. The c-Kit gene encodes the mast cell growth factor receptor. III. Membrane Associated Non-Receptor Tyrosine Kinases a. The v-src gene was the first identified oncogene. b. The c-Src gene is the archetypal protein tyrosine kinase. c. The Lck gene was isolated from a T cell tumor line (LYSTRA cell kinase) and associated with the CD4 and CD8 antigens of T cells. IV. G-Protein Coupled Receptors a. The Mas gene, identified in mammary carcinoma. V. Membrane Associated G-Proteins a. The ras gene is one of the most frequently disrupted genes in colorectal carcinomas. VI. Serine/Threonine Kinases a. The Raf gene, involved in the signaling pathway of most RTKs. It is likely responsible for threonine phosphorylation of MAP kinase following receptor activation. VII. Nuclear DNA-Binding/Transcription Factors a. A disrupted human c-Myc gene has been found to be involved in numerous hematopoietic neoplasias. a. The Fos gene, identified in the feline osteosarcoma virus. b. The p53 gene was originally identified as a major nuclear antigen in transformed cells, and is the single most identified mutant protein in human tumors. Of particular interest is the ras family of proto-oncogenes. There are three homologs of this gene, H-ras, K-ras, and N-ras, and these have been detected in more human tumor types and at a higher frequency than any other oncogene (Anderson et al., 1992). They acquire transforming activity by a point mutation in their coding sequence. Invivo, activating point mutations have been observed in codons 12, 13, 61, 117, and 146 (Anderson et al., 1992). Activated ras proto-oncogenes have been detected in colon carcinomas (47%), pancreatic carcinomas (81%), lung adenocarcinomas (32%), cholangiocarcinomas (88%), certain types of thyroid tumors (56%), endometrial adenocarcinomas (47%), mucinous adenocarcinomas of the ovary (75%), squamous cell carcinomas (SCC) at sun-exposed sites (47%), and SCC assoc with tobacco/quid chewing (35%) (Anderson et al., 1992). In human tumors, the activation of ras genes occurs at various stages of carcinogenesis (Anderson et al., 1992). In addition to being observed in malignant tumors, ras genes have also been noted in adenomas, which can progress to a malignant tumor (Anderson et al., 1992). They have also been detected in several benign tumors like human skin keratocanthomas and basal-cell carcinomas (Anderson et al., 1992). It can be inferred from this that “ras activation is not sufficient in all cases to promote the continual growth of a tumor, and subsequent accumulation of additional genetic damage is required to make the tumor invasive and metastatic”(Anderson et al., 1992). Other than ras oncogenes, numerous other proto-oncogenes have been shown to be activated in human and to a lesser extent in rodent tumors (Anderson et al., 1992). The following is a list of non-ras proto-oncogenes causing cancer (Anderson et al., 1992). a. Neuroblastoma: N-myc amplification in more than 50 % of the tumors. b. Breast adenocarcinomas: e-myc amplification with hormone receptor negativity, high tumor grade and older patient age. Amplification of int-2 and hst-1 in steroid-positive tumors. HER2/neu amplified in both node-negative and node-positive breast cancers. c. Gastric adenocarcinomas: C-myc, hst-1, HER2/neu, and K-ras. d. Lung tumors: L-myc, N-myc, C-myc. e. Esophageal squamous carcinomas: Coamplification of int-2/hst-1 genes was observed in 28% and 52% of esophageal squamous carcinomas and in 30% and 100% of lymph node metastases. Usually, proto-oncogene amplification is usually associated with progression of neoplasia rather than the initiation of carcinogenesis. However, HER2/neu has been observed to be amplified in early clinical stages of some mammary tumorigenesis (Anderson et al., 1992). Although protein overexpression almost always accompanies gene amplification, some tumors with a single copy of a proto-oncogene may overexpress the protein (Anderson et al., 1992). “The role of gene overexpression, in the absence of gene amplification, in the tumorigenic process is unclear”(Anderson et al., 1992). The overexpression could be due to mutations in other genes or due to alterations in the regulatory regions of a proto-oncogene (e.g. HER2/neu in mammary tumors or myc genes in lung tumors) (Anderson et al., 1992). Therefore, “amplification of proto-oncogenes and possibly gene overexpression in the absence of gene amplification are important events in the development of many human tumors”(Anderson et al., 1992). Conclusion Primary human cancers harbor activated alleles of proto-oncogenes, which are classified into various types based on their normal function within cells or upon sequence homology to other known proteins. Of all types, the ras family of proto-oncogenes has been detected in more human tumor types and at a higher frequency than any other oncogene. They have been implicated in colon carcinomas, pancreatic carcinomas, lung adenocarcinomas, cholangiocarcinomas, certain types of thyroid tumors, endometrial adenocarcinomas, mucinous adenocarcinomas of the ovary, and squamous cell carcinomas. The non-ras proto-oncogenes have been implicated in neuroblastoma, breast adenocarcinomas, gastric adenocarcinomas, lung tumors and esophageal squamous carcinomas. Usually, proto-oncogene amplification is usually associated with progression of neoplasia rather than the initiation of carcinogenesis. However, the role of gene overexpression, in the absence of gene amplification, in the tumorigenic process is unclear References Anderson, M.W, Reynolds, S.H, You, M, Maronpot, R.M (1992). Role of proto-oncogene activation in carcinogenesis. Environ Health Perspect. 98:13-24. Haber, D.A (2006). Molecular Genetics of Cancer: Oncogenes and Proto-oncogenes. Retrieved March 18, 2007, from http://www.medscape.com/viewarticle/534487 National Science Teachers Association (2001). Proto-oncogenes and Cancer. Retrieved March 18, 2007, from, http://web.indstate.edu/thcme/mwking/oncogene.html Read More