Molecular defects - the causes of malignant cell division

Causes of malignant cell division

Molecular defects - the causes of malignant cell division.

Molecular defects



The cause of the division of malignant cells in most cases are gene mutations. These mutations change the amount or function of synthesized proteins that regulate cell growth, DNA division and repair. Two large categories of genes whose mutations affect oncogenesis are represented by oncogenes and tumor suppression genes.


Oncogenes are abnormal forms of normal genes (proto-oncogenes) that regulate cell growth. Mutations of these genes can cause direct and long-term stimulation of molecular-biological mechanisms (for example, intracellular signal transduction pathways, transcription factors, secretion of growth factors) that control cell growth and division.


More than 100 oncogenes are known that can contribute to the tumor transformation of human cells.For example, the ras gene encodes a RAS protein that regulates cell division. Mutations in the gene can cause inadequate activation of the RAS protein, leading to uncontrolled cell growth. It is a fact that the RAS protein abnormality occurs in 25% of human malignant diseases. Other oncogenes are involved in the pathogenesis of certain cancers. These are various protein kinases (bladder cancer, breast cancer), bcr-abl (chronic myeloid leukemia, B-cell acute lymphoblastic leukemia), C-tus (small cell lung cancer), N-myc (small cell lung cancer, neuro-roblastoma ) C-erb B-2 (breast cancer). Specific oncogenes are of great importance for the diagnosis, treatment and prognosis (see the description of various types of tumors).


Oncogenes are usually the result of acquired mutations of somatic cells (for example, as a result of exposure to chemical carcinogens), gene amplification (increase in the number of copies of the normal gene), or the introduction of viral genetic elements into the host DNA. Sometimes, a germ cell line mutation results in a vertical transmission and a high likelihood of developing progeny cancer.


Tumor suppression genes are innate genes and play an important role in cell division, DNA repair and are necessary to control abnormal growth signals in cells. If congenital or acquired mutations occur in these genes that block their function, mutations in other genes proceed uncontrollably, leading to neoplastic transformation.


As with most genes, there are 2 alleles encoding each gene for tumor suppression. With a congenital defective copy of one gene, a person lives with only one functioning allele of the gene for tumor suppression. If a mutation occurs in another allele, the normal protective mechanisms of the suppression tumor gene are lost, thereby breaking control of protein synthesis or DNA damage, leading to the development of cancer. For example, the retinoblastoma (RB) gene encodes a pRB protein that regulates the cell cycle, stopping DNA replication. Mutations of the RB gene occur at 30-40% of all human malignant tumors, allowing the affected cells to divide continuously.


Another mechanism that leads to dysfunction and transcription of tumor suppressor genes is the abnormal methylation of the promoter region of these genes, which inhibits gene transcription.A more pronounced degree of abnormal methylation and a greater number of affected genes cause more malignant tumors, which is associated with a short survival rate for cancer of the lung, bladder and prostate gland. In vitro experiments have shown that correcting abnormal methylation leads to reversion to a non-cancerous, non-proliferative phenotype, thereby demonstrating a potential therapeutic effect.


Another important regulatory protein, p53, prevents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or damaged p53 allows cells with abnormal DNA to survive and divide. Mutations pass to the daughter cells, which leads to a high probability of neoplastic transformation. The p53 gene has disorders in many human malignant tumors.


Coarse chromosomal abnormalities result from deletions, translocations, or duplications. If these lesions activate or inactivate genes, leading to a predominance of proliferation over normal cells, this can contribute to the development of the tumor.Chromosomal abnormalities are present in a number of human malignant tumors and in certain hereditary diseases (Bloom, Fanconi, Down syndrome).


In many malignant diseases, several mechanisms described above are likely to be involved, leading to neoplastic conversion. For example, the following genetic events take part in the development of a family polyposis tumor: epithelial hyperproliferation (loss of a suppressor gene on chromosome 5), early adenoma (changes in DNA methylation), intermediate adenoma (hyperactivity of the oncogene ras), late adenoma (loss of a suppressor gene on chromosome 18 ), and ultimately cancer (gene loss on chromosome 17). Subsequent genetic changes may be necessary for metastasis.


As in the case of oncogenes, mutation of tumor suppression genes in germ cell lines can result in vertical transmission and a high likelihood of developing cancer in the offspring.


Telomeres are nucleoprotein complexes that complete the ends of chromosomes and maintain their integrity. Telomeres shorten (with age), resulting in impaired replication, increased genetic instability, and potential tumor formation.Telomerases are enzymes that provide for the synthesis of telomeres and their maintenance, thus telomerases can potentially provide cell immortality. Telomerase activity may contribute to the development of a tumor through numerous complex mechanisms. So, molecular defects are the causes of the division of malignant cells.

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