Oncogenes o Genes that promote autonomous cell growth in cancer cells are called oncogenes proto-oncogenes o unmutated cellular

counterparts of oncogenes are called protooncogenes Steps involved in cell proliferation under physiologic conditions o The binding of a growth factor to its specific receptor o Transient and limited activation of the growth factor receptor, which, in turn, activates several signal-transducing proteins on the inner leaflet of the plasma membrane o Transmission of the transduced signal across the cytosol to the nucleus via second messengers or by a cascade of signal transduction molecules o Induction and activation of nuclear regulatory factors that initiate DNA transcription o Entry and progression of the cell into the cell cycle, ultimately resulting in cell division Growth Factors. o Autocrine loop Many cancer cells acquire the ability to synthesize the same growth factors to which they are responsive Many glioblastomas secrete platelet-derived growth factor (PDGF) and express the PDGF receptor (MCQ) many sarcomas make both transforming growth factor (TGF-) and its receptor. (MCQ) o Products of other oncogenes that lie along many signal transduction pathways cause overexpression of growth factor genes, thus forcing the cells to secrete large amounts of growth factors Product of RAS gene cause overexpression of genes to produce TGF-. (MCQ) Growth Factor Receptors. Several oncogenes can encode growth factor receptors How mutant growth factor receptors deliver continuous mitogenic signals to the cell, even in the absence of growth factor ? o growth factor receptors are transmembrane proteins with an external ligand-binding domain and a cytoplasmic tyrosine kinase domain o In the normal forms (i.e without mutation) of these receptors, the kinase is transiently activated by binding of the specific growth factors, followed rapidly by receptor dimerization and tyrosine phosphorylation of several substrates that are a part of the signaling cascade. o The oncogenic versions of these receptors are associated with constitutive dimerization and activation without binding to the growth factor. Different mechanisms by which growth factor receptors can be constitutively activated in tumors o Mutations

o gene rearrangements o overexpression RET proto-oncogene o a receptor tyrosine kinase (MCQ) o exemplifies oncogenic conversion via mutations and gene rearrangements o RET protein a receptor for the glial cell linederived neurotrophic factor it promote cell survival during neural development. (MCQ) o RET is normally expressed in neuroendocrine cells, such as parafollicular C cells of the thyroid, adrenal medulla, and parathyroid cell precursors. o Point mutations in the RET proto-oncogene are associated with dominantly inherited MEN types 2A and 2B (MCQ) familial medullary thyroid carcinoma (MCQ) o affected individuals inherit the RET mutation in the germline. o Sporadic medullary carcinomas of the thyroid are associated with somatic rearrangements of the RET gene FLT3(MCQ) o the gene encoding the FMS-like tyrosine kinase 3 receptor o Point mutations lead to constitutive signaling o detected in myeloid leukemias(MCQ) entire cytoplasmic domain of the PDGF receptor is fused with a segment of an ETS family transcription factor o seen in chronic myelomonocytic leukemias with the (5;12) translocation, result in permanent dimerization of the PDGF receptor. (MCQ) constitutively activating mutation in the receptor tyrosine kinase cKIT or PDGFR(MCQ) Seen in greater than 90% of gastrointestinal stromal tumors (MCQ) These mutations are amenable to specific inhibition by the tyrosine kinase inhibitor imatinib mesylate. (MCQ) overexpression of epidermal growth factor (EGF) receptor family ERBB1 o normal form is EGF receptor gene o overexpressed in (MCQ) squamous cell carcinomas of the lung glioblastomas head and neck tumors. ERBB2 gene (also called HER-2/NEU) (MCQ) o member of the EGF receptor family o amplified in (MCQ) breast cancers human adenocarcinomas arising within the ovary, lung, stomach, and salivary glands o Herceptin(MCQ)

a recombinant humanized anti-ERBB2 monoclonal antibody

Signal-Transducing Proteins o strategically located on the inner leaflet of the plasma membrane o they receive signals from outside the cell (e.g., by activation of growth factor receptors) and transmit them to the cell's nucleus. o most well-studied example of a signal-transducing oncoprotein is the RAS family of guanine triphosphate (GTP)-binding proteins (G proteins) RAS Oncogene. o three RAS genes, in the human genome (HRAS, KRAS, NRAS), o Point mutation of RAS family genes is the single most

common abnormality of proto-oncogenes in human tumors. (MCQ)

o Approximately 15% to 20% of all human tumors contain mutated versions of RAS proteins o RAS point mutation is seen in 90% of pancreatic adenocarcinomas and cholangiocarcinomas 50% of colon, endometrial, and thyroid cancers 30% of lung adenocarcinomas and myeloid leukemias. o Type of RAS mutation carcinomas (particularly from colon and pancreas) have mutations of KRAS (MCQ) bladder tumors have HRAS mutations (MCQ) hematopoietic tumors bear NRAS mutations. (MCQ) o Mechanism of RAS in oncogenesis Abrogation of RAS function blocks the proliferative response to EGF, PDGF, and CSF-1. Normal RAS proteins are tethered to the cytoplasmic aspect of the plasma membrane endoplasmic reticulum membrane Golgi membranes. RAS can be activated by growth factor binding to receptors at the plasma membrane. RAS is a member of a family of small G proteins that bind GTP and GDP Normally RAS proteins flip back and forth between an excited signal-transmitting state and a quiescent state. In the inactive state, RAS proteins bind GDP Stimulation of cells by growth factors leads to exchange of GDP for GTP and subsequent conformational changes that generates active RAS The activated RAS stimulates downstream regulators of proliferation, such as the mitogen-activated protein (MAP)

kinase cascade, which floods the nucleus with signals for cell proliferation. (MCQ) The orderly cycling of the RAS protein depends on two reactions nucleotide exchange (GDP by GTP), which activates RAS protein (MCQ) o catalyzed by a family of guanine nucleotidereleasing proteins GTP hydrolysis, which converts the GTP-bound, active RAS to the GDP-bound, inactive form o accelerated by GTPase-activating proteins (GAPs). o GAPs function as brakes that prevent uncontrolled RAS activity. (MCQ) o neurofibromin 1, a GAP, is associated with familial neurofibromatosis type 1 (MCQ) Mutations in BRAF, o It is one of the members of the RAF family o detected in more than 60% of melanomas and in more than 80% of benign nevi (MCQ) o dysregulation of the RAS/RAF/MAP kinase pathway may be one of the initiating events in the development of melanomas o BRAF mutations alone lead to oncogene-induced senescence giving rise to benign nevi rather than malignant melanoma. o oncogene-induced senescence is a barrier to carcinogenesis that must be overcome by mutation and disabling of key protective mechanisms, such as those provided by the p53 gene Alterations in Nonreceptor Tyrosine Kinases o non-receptor-associated tyrosine kinases normally function in signal transduction pathways that regulate cell o c-ABL tyrosine kinase (MCQ) seen in CML and some acute lymphoblastic leukemias ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22 where it fuses with the BCR gene (MCQ) The resultant chimeric gene encodes a constitutively active, oncogenic BCR-ABL tyrosine kinase. (MCQ) imatinib mesylate, inhibits the BCR-ABL kinase. (MCQ) o nonreceptor tyrosine kinases are activated by point mutations that abrogate the function of negative regulatory domains that normally hold enzyme activity in check o polycythemia vera and primary myelofibrosis highly associated with activating point mutations in the tyrosine kinase JAK2 (MCQ) aberrant JAK2 kinase in turn activates transcription factors of the STAT family, which promote the growth

factorindependent proliferation and survival of the tumor cells. (MCQ) o JAK2 inhibitors in myeloproliferative disorders, Ruxolitinib (MCQ) Used against JAK1/JAK2 for psoriasis, myelofibrosis and rheumatoid arthritis Tofacitinib (MCQ) Used against JAK3 for psoriasis and rheumatoid arthritis. Transcription Factors. o transcription factors that regulate the expression of growthpromoting genes, such as cyclins o MYC, MYB, JUN, FOS, and REL oncogenes o The MYC Oncogene. (MCQ) is expressed in virtually all eukaryotic cells (MCQ) belongs to the immediate early response genes, which are rapidly induced when quiescent cells receive a signal to divide MYC is involved in carcinogenesis by activating genes that are involved in proliferation. Dysregulation of MYC expression resulting from translocation of the gene occurs in Burkitt lymphoma, a Bcell MYC is amplified in some cases of breast, colon, lung (MCQ) N-MYC is amplified in neuroblastomas(MCQ) L-MYC is amplified in small-cell cancers of the lung (MCQ) Cyclins and Cyclin-Dependent Kinases. o the orderly progression of cells through the various phases of the cell cycle is orchestrated by cyclin-dependent kinases (CDKs) o CDKs are activated by binding to cyclins o CDK-cyclin complexes phosphorylate crucial target proteins that drive the cell through the cell cycle. o cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDK. (MCQ) o The cell cycle is a relay race in which each lap is regulated by a distinct set of cyclins, and as one set of cyclins leaves the track, the next set takes over o Most common Cyclin mutation in many cancers is cyclin D or CDK4 (MCQ) o Amplification of the CDK4 gene occurs in melanomas, sarcomas, and glioblastomas. (MCQ) Cyclin-Dependent Kinase Inhibitors o silence the CDKs o exert negative control over the cell cycle. o The CIP/WAF family of CDKIs composed of three proteins p21 (CDKN1A) p27 (CDKN1B) p57 (CDKN1C),

o INK4 family of CDK1s has selective effects on cyclin D/CDK4 and cyclin D/CDK6 made up of p15 (CDKN2B) p16 (CDKN2A) p18 (CDKN2C) p19 (CDKN2D) Germline mutations of p16 (CDKN2A) are associated with melanoma (MCQ) Cell cycle checkpoints o maintain genomic integrity o G1/S transition check point G1/S checkpoint prevents the replication of cells that have defects in DNA, (MCQ) Mechanism S phase is the point of no return in the cell cycle. Before a cell makes the final commitment to replicate, the G1/S checkpoint checks for DNA damage if damage is present, the DNA-repair machinery and mechanisms that arrest the cell cycle are put in motion. The delay in cell cycle progression provides the time needed for DNA repair if the damage is not repairable, apoptotic pathways are activated to kill the cell. o G2/M check point monitors the completion of DNA replication (MCQ) checks whether the cell can safely initiate mitosis and separate sister chromatids. (MCQ) This checkpoint is particularly important in cells exposed to ionizing radiation. Cells damaged by ionizing radiation activate the G2/M checkpoint and arrest in G2 (MCQ) defects in this checkpoint give rise to chromosomal abnormalities. (MCQ) o cell cycle checkpoints require sensors of DNA damage, signal transducers, and effector molecules sensors are proteins of the RAD family ataxia telangiectasia mutated (ATM) family transducers are proteins of the CHK kinase families