Role of three cancer "master genes" p53, bcl2 and c-myc on the apoptotic process.

Chiarugi V, Ruggiero M.

Laboratory of Molecular Biology, University of Florence, Italy.

We review some of the most recent developments concerning three genes involved in human cancer: p53, bcl2 and c-myc. Recent data have demonstrated that the bcl2 gene protects tumor cells from apoptosis induced by a variety of agents, including ionizing radiation, and is thus related to resistance to DNA-damaging therapeutic agents. The p53 tumor suppressor gene, however, has been related with growth arrest, apoptosis and thus with selective sensitivity to the killing effects of ionizing radiation and DNA-damaging drugs. This functional antagonism between the two genes was recently substantiated in molecular terms by demonstration of reciprocal down-regulation due to the presence of a p53-dependent transcription silencer in the untranslated region of the bcl2 gene. Growth arrest in the G1 phase of the cell cycle and induction of apoptosis are two distinct and dissectable functions of p53: bcl2 is able to antagonize the induction of apoptosis by p53, but not the growth arrest in G1. However, coexpression of bcl2 and of the oncogene c-myc efficiently antagonizes effects of p53 on G1 arrest and apoptosis, thus suggesting a cooperation between the two oncogenes. In addition, c-myc disrupts other functions of genetic control in the early G1 phase of the cell cycle including the expression of D1 cyclin. We believe that knowledge of the functional/molecular interactions between these three genes involved in human cancer is a fundamental prerequisite to improve the knowledge on prognosis and to design innovative therapeutic approaches.

PMID: 8693593 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/8693593

Cancer

Cancer (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.

Cancer may affect people at all ages, even fetuses, but the risk for most varieties increases with age.^[1] Cancer causes about 13% of all deaths.^[2] According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007.^[3] Cancers can affect all animals.

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers are usually affected by complex interactions between carcinogens and the host's genome. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly recognized as important.

Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are then inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

Diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular abnormalities in certain tumors, and which minimize damage to normal cells. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.