In this article we will discuss about the development of tumour suppressor genes.
Inactivation of tumour suppressor genes also contributes to development of tumours. Normally, tumour suppressor genes act to inhibit cell proliferation and tumour development. When these genes are inactivated or lost they lead to abnormal proliferation of tumour cells. The first tumour suppressor gene was identified through studies on retinoblastoma.
Through studies on patients with retinoblastoma that have survived, it was found that some cases of retinoblastoma are inherited, 50% of the children of an affected parent have a chance to develop retinoblastoma. According to Mendelian inheritance, this suggests transmission of retinoblastoma by a single dominant gene.
Although it is a dominant trait, inheritance of the gene is not sufficient to convert a normal retinal cell into a tumour cell. That is because tumour cells have further requirements in addition to inheriting the gene.
In 1971 Knudson found out that development of retinoblastoma requires two mutations that would make both copies of the gene, that is the Rb tumour suppressor gene, to become non-functional. Thus both alleles of Rb on the two homologous chromosomes must be inactivated to induce retinoblastoma. One defective copy of Rb is not sufficient for tumour development.
That Rb gene may be considered as a negative regulator of tumorigenesis was deduced from study of deletions in chromosomes 13 and 14 displaying loss of Rb gene. Gene mapping studies confirmed that the loss of normal alleles of Rb resulted in tumour development, suggesting Rb’s function as a tumour suppressor gene.
Gene transfer experiments made it clear that introduction of a normal Rb gene into retinoblastoma cells reverses their tumorigenecity, thus indicating activity of Rb as a tumor suppressor.
Later studies have shown that Rb is lost or inactivated in many other human cancers, such as bladder, breast and lung carcinomas. Additional tumour suppressor genes that contribute to development of tumours have subsequently been identified.
Studies show that tumour suppressor genes are involved in the development of both inherited and non-inherited cancers of humans. Mutations in the tumour suppressor genes appear to be the most common molecular alterations resulting in human tumour development.
Subsequently,p53 was identified as the second tumour suppressor gene that is inactivated in a wide variety of human cancers, including leukemia’s, lymphomas, brain tumours, sarcomas, and carcinomas of several tissues. Mutations in p53 are said to play a role in about 50% of all cancers, making it the most common target for genetic alterations in human cancers.
Cancer cells that have lost p53 function cannot undergo apoptosis and they become highly resistant to further treatment. This may be the primary reason why tumours that typically lack a functional p53 gene (example melanoma, colon cancer, prostate cancer, pancreatic cancer) respond much more poorly to radiation and chemotherapy than tumours that have a wild-type copy of this gene (example testicular cancer, childhood acute lymphoblastic leukemias).
Like p53, the INK4 and the PTEN tumour suppressor genes are also frequently mutated in several human cancers. Cancer of the colon may have mutation in two other tumour suppressor genes, namely, APC and MADR2. Additional tumour suppressor genes have been indicated in the development of brain tumours, pancreatic cancers and basal cell carcinoma of skin, as well as in several rare inherited cancers.
Survivin Protein and Cell Division:
Survivin is a recently discovered (1997) small-sized protein that is essential for cell divison and also acts as an inhibitor for apoptosis. Because of its involvement in promoting cell proliferation and preventing apoptosis, it is considered to be the protein that interfaces life and death.
Survivin has been found to be abundant in human cancers, where it has the potential as a prognostic marker for cancer, and is also a target for chemotherapy. The survivin gene, about 15 kb long is located on chromosome 17 at position q25.
Survivin is expressed in embryos and juveniles, but has not been detected in quiescent cells and terminally differentiated adult tissue. In actively proliferating cells, survivin expression is regulated through the cell cycle, such that it is absent in G1 and S phases but with a peak level in G2 and in mitosis.
Attempts to localise survivin in proliferating HeLa cells using fluorochromes have indicated presence of survivin during prophase to prometaphase stages of cell division at the centromeres and associated with the microtubules.
Not much is known about its prognostic importance. Importantly however, is the finding that survivin is expressed in many human malignancies, both solid and haematological and seems to be one of the most tumour-specific of all human gene products.