Genome of Hepatitis B Virus VIRAL ONCOGENE Dr. Yahwardiah Siregar, PhD Dr. Sry Suryani Widjaja, Mkes Biochemistry Department
Proto Oncogen and Oncogen Oncogen Proteins that possess the ability to cause cellular transformation. Act in a dominant fashion, either overexpression or activating mutations. Cellular transformation. morphologic changes, loss of contact inhibition, anchorage independent growth, ability to form tumors when transplanted into nude mice.
Proto-oncogene. Potential to become activated into a cancer causing oncogene. Have been found in all multicellular organisms. Would be involved : basic essential functions of the cell related to control of cell proliferation and differentiation. In normal cell : expression is tightly controlled.
Cell Cycle
Cell-cycle control system is based on cyclically activated protein kinases : -Cdks ( cyclin dependent kinases ) -Cyclins ( cdk regulator protein ),without cyclins cdk is inactive.
Proto-oncogenes 1.Growth Factors Stimulate cells in stationary stage to enter the cell cycle. Occurs in a two stage process : Stimulation to proceed into G 1 provided by PDGF,EGF,followed by progression factors :IGF to progress through the cell cycle. Action via autocrine and paracrine model.
2.Growth factor receptors Link the information from extracellular environment (GF) to a number of different intracellular signaling pathways. The most important : transmembrane receptor tyrosine kinases.
3. Signal transducers. Cytoplasmic nonreceptor tyrosine kinases. Proteins with enzyme activity such as phospholipase Cγ, PI3-K Adaptor proteins : Grb2 SH2 and SH3 domain. Three major pathways : PI3-kinase (PI3-K/AKT pathway,ras/mitogen-activated protein kinase (MAPK) pathway,jak/stat pathway.
4. Nuclear proto-oncogne and transcription factors. Involved in the control of gene expression by their action on DNA itself Final site of action for messages sent from GF. Level at which control of growth and proliferation.
animasi
Apoptosis Programmed cell death Intracellular machinery responsible for apoptosis is called caspases. Caspases Synthesized in the cell as inactive precursor called procaspases Usually activated by cleavage at aspartic acids by other caspases.
Mechanisms of oncogeneactivation 1. Structural alteration. Point mutations Chromosomal translocation Truncated form of protein (transition mutation) 2. Amplification 3. Deregulated expression Insertional mutagenesis Translocation.
Tumor suppressor genes Play an important role in tumorigenesis. Involved in the control of abnormal cell proliferation. Loss or inactivation : association with the development of malignancy.
Viral Oncogene Three major mechanisms by which an infectious agent can cause cancer : 1. Persistent infection chronic inflammation repeated cycles of cell damage and cellular proliferation accumulate genetic mutations initiation and promotion of cancer.
2.Direct participation of infectious agents in the transformation of the cell through activation of cellular oncogene pathway. 3. Relevant to HIV : infection may result in 3. Relevant to HIV : infection may result in immunosuppression and decreased recognition of infected or transformed cell by host immune system.
Retroviruses
Gene TRANSCRIPTION Primary transcript Degradation NUCLEUS mrna MODIFICATION / PROCESSING Degradation Transport CYTOPLASM mrna Protein TRANSLATION Active inactive degradation Degradation
Mechanisms of retroviral oncogenesis. 1. Slowly transforming viruses. Insertional mutagenesis 2. Acutely transforming viruses. Oncogene transduction 3. Trans-acting retroviruses. Affect expression or function of cellular growth and differentiation genes. HTLV1 ( the only human retrovirus known to directly cause cancer).