分子生物学分子生物学 (28).pdf

Molecular basis of diseaseChapter 1111.2 Cell-related factors cause abnormal gene expression and cause disease11.2 Cell-related factors cause abnormal gene expression and cause disease11.2.1Abnormal signal between cells leads toabnormal gene expression and causes disease11.2.2 Intracellular factors cause abnormal geneexpression and cause diseaseAbnormal expression of alpha-fetoprotein(AFP)and tumorAFP is only expressed in the embryonicstage,protecting the fetus from maternalimmune attacks.The cis-acting elements ofits genes can be combined by oncogeneproducts to activate transcription.11.2.1Abnormal signal between cells leads to abnormal gene expression and causes diseaseSchematic diagram of the amino acid sequence and secondary structure of human alpha-fetoproteinIncreased expression of hepatocellular oncogeneAbnormal expression of AFPInhibits the expression of TNF and its receptors on lymphocytes or liver cancer cellsLiver cancer cells evade the bodys immune surveillance and proliferate in large numbersSilicosis is the most common type of pneumoconiosis.It is caused by long-terminhalation of large amounts of free silica dust and is a disease mainly caused byextensive nodular fibrosis in the lungs.Silicosis is the most common,fastest-growing,and most harmful type ofpneumoconiosis.There are about 20,000 new cases of pneumoconiosis every year in China.Therefore,the prevention and treatment of pneumoconiosis is a difficult task.SilicosisSilicaduststimulationpulmonarybronchialepithelium,alveolar macrophages secretion of TGF-1 fibroblasts mitogenic and ECM protein gene expression increased ECM silicosisThe human body is composed of multiple cells,multiple tissues and organs.The various lifeactivities of any one cell,including gene expression and protein synthesis,cannot be carriedout in isolation.The normal intercellular signal can ensure the normal time specificity,spatial specificity andnormal expression level of gene expression.Wrong intercellular signal will destroy the temporal and spatial specificity of gene expression,make post-embryonic cells synthesize embryonic protein,or make one cell synthesize anothercell-specific protein,and make the gene expression level too high or too low,these will lead todisease.11.2.2 Intracellular factors cause abnormal gene expression and cause diseaseDiabetic cardiomyopathy refers to a myocardial disease that occurs in patientswith diabetes and cannot be explained by hypertensive heart disease,coronaryatherosclerotic heart disease,and other heart disease changes.On the basis of metabolic disorders and microvascular disease,the diseasecauses extensive myocardial necrosis of the heart muscle,subclinical cardiacdysfunction,and eventually progresses to heart failure,arrhythmia andcardiogenic shock.Diabetic cardiomyopathy 1.Abnormal intracellular signals-Diabetic cardiomyopathy caused by persistent high blood sugarHyperglycemia DAG Activate PKC Increase the expression of angiotensin-convertingenzyme(ACE)Angiotensin II Myocardialremodeling and myocardial hypertrophy2.Abnormal DNA methylation leads to abnormal gene expressionDNA methylation is catalyzed by DNA methyltransferases(DNMT)using S-adenosylmethionine as a donor to addmethyl groups to the bases of DNA molecules.Its main forms include 5-methylcytosine,6-methyladenine,7-methylguanine,and 5-methylcytosine is the most commonmethylated form.CpG dinucleotide is the main site of DNA methylation.The methylation of CpG sites in the gene promoter region affects genetranscription activity in three ways:(1)DNA sequence methylation directly hinders the binding of transcriptionfactors(2)The methyl CpG binding protein binds to the methylated CpG site andinteracts with other transcription repressors(3)DNA methylation can change chromatin structure,hinder the binding oftranscription factors and their regulatory sequences,and inhibit genetranscription3.Abnormal modification of histoneHistone methylation,acetylation,deacetylation,and other modifications affect the compression andtightness of chromatin and regulate gene expression.4.Gene expression changes caused by non-coding RNALong-chain non-coding RNA(lncRNA)Short-chain non-coding RNA(siRNA,miRNA)Structure affecting chromatin Regulate transcription Participate in RNA processing and modification Participate in the process of mRNA stabilization and translation regulation Affect protein stability and transportsummaryThrough the study of the above knowledge,we have learned themolecular basis of the onset of certain diseases,which are relatedto abnormal gene expression caused by abnormal signal betweencells,and abnormal gene expression caused by intracellular factors.Thank you!