Wednesday, November 2, 2011

Cancer and Oncogenes

Cancer is a diverse group of diseases with one common characteristic: unchecked cellular replication.  Via several potential mechanisms, cancer cells are able to avoid all of the checkpoints involved in cell growth and division, thus enabling them to divide more frequently or indefinitely.  Many events can lead to the development of a cancer cell, including inheritance of mutated DNA or the activity of a carcinogen, or a chemical agent that leads to the development of cancer.

Gene expression is often deregulated in cancer cells such that some genes are overexpressed, while others are underexpressed.  Genes that can be mutated to lead to an upregulation of activity and lead to the development of a cancer cell are termed proto-oncogenes.  When these proto-oncogenes are actually mutated, they are considered oncogenes.

An oncogene is often a gene involved in regulating cell division and drive the cell cycle.  When they are overexpressed, such as during cancer, they can push the cell to divide more frequently and, with further mutations, transform the cell such that it divides without restriction.

Oncogenes were first discovered in viruses, specifically in Rous Sarcoma Virus (RSV), a retrovirus that encodes a homologue to cellular src kinase (the viral form called v-src).  Tumors in birds caused by RSV are the result of v-src causing unregulated cellular proliferation.  Large amounts of research into this area has identified cellular src kinase as a proto-oncogene that, when mutated to become constitutively active, becomes an oncogene and can drive cancer development.  Interestingly, viruses have highlighted a number of cellular oncogenes and pathways that are improperly regulated in cancer.  Over 20 viral oncogenes have been identified to date.

Cellular proto-oncogenes (the genes before they become oncogenes) can promote cellular proliferation and the development of cancer in several ways.  One of these ways is to be overexpressed and function when the gene product really shouldn't function.  This is the case with proteins such as myc and growth factor receptors.  With overexpression of these proteins, there is the potential for amplified signaling through these pathways that can push the cell to divide more than it normally does, leading to the development of cancer.  An additional mechanism whereby a proto-oncogene can become an oncogene is via mutation that leads to improper regulation, such as constitutive activity.  A classical example of this type of phenomenon is via Ras, which when mutated is constitutively active and cannot hydrolyze an attached GTP to inactivate.  Thus, Ras remains active and cannot be "turned off."  This constant activity of Ras results in  signal transduction to the nucleus of the cell and pushes the cell to divide through transcription of several genes involved in cell division.

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