20.2 Oncogenes Flashcards
specific genes that can induce cell transformation (process of converting normal cells to tumor cells) → they can induce cancer
oncogenes
studies of () led to identification of cellular oncogenes involved in developement of non-virus-induced cancers
retroviral oncogenes
() transforms chicken embryo fibroblasts in culture and induces sarcomas
Rous sarcoma virus (RSV)
RSV is closely related to () replicates in the same cells without inducing transformation → RSV contained specific genetic information for transformation
avian leukosis virus (ALV)
studies of RSV mutants revealed a single gene called () responsible for RSV tumor induction
src
many oncogenes encode components of signaling pathways that stimulate ()
cell proliferation (e.g. src, encoding Ras and Raf)
studies involving the () found that even though a mouse was injected only with viral genes responsible for replication (i.e. no genes inducing transformation), it developed leukemia
Abelson leukemia virus
the Abelson leukemia virus was found to induce leukemia due to the presence of an oncogene called ()
abl
explain how viral oncogenes can have cellular origins
a host cell gene that can drive cell proliferation occasionally becomes incorperated into a viral genome → yields a highly oncogenic virus with an oncogene derived from the host cell
normal genes from which retroviral oncogenes originated
proto-oncogenes
oncogenes are () of the proto-oncogenes
abnormally expressed or mutated forms
proto-oncogenes often encode proteins in the signaling pathways that () → these genes are triggered by growth factors
control normal cell proliferation (e.g. src, ras, raf)
retroviral oncogenes differ from proto-oncogenes in the ff aspects:
- transcription in viral oncogenes is controlled by viral promoters and enhancers
- oncogenes often encode proteins that differ in structure and function from normal proteins
- loss of regulatory domains generates in oncogenes proteins that function in an unregulated manner
transcription in viral oncogenes is controlled by viral promoters and enhancers; this results in the oncogenes being ()
expressed at much higher levels than proto-oncogenes or in the wrong cells
oncogenes such as Raf are expressed as fusion proteins with () at the amino terminus
viral sequences
deletion of () leads to raf protein kinase hyperactivity → drives abnormal cell proliferation and then cell transformation
regulatory domain
many oncogenes differ from proto-oncogenes by () → single amino acid substitutions in proteins, which then lead to unregulated protein activity
point mutations
gene transfer experiments found evidence for involvement of cellular oncogenes in human tumors (not induced by viruses)
DNA from a human bladder carcinoma was found to induce transformation of mouse cells in culture → tumor contained an oncogene
the first human oncogene identified was the homolog of the (1) of the (2)
- rasH oncogene
- Harvey sarcoma virus
three members of the ras gene family () are the oncogenes most frequently encountered in human tumors
rasH, rasK, rasN
mutations of ras oncogenes maintain the ras proteins in the ()
active GTP-bound conformation
mutated ras proteins do not respond to GAP (GTPase-activating protein) → ()
GTP bound to Ras is not hydrolyzed to GDP to inactivate Ras
many cancer cells have () → lead to generation of oncogenes
abnormal chromosome structures, including translocations, duplications, and deletions
in Burkitt’s lymphoma, chromosome translocation inserts () oncogene into an (2), where it is expressed in an unregulated manner
- c-myc
- immunoglobulin locus
translocation of abl proto-oncogene leads to production of a () → unregulated activity of Abl tyrosine kinase → cell transformation
bcr/abl fusion protein
oncogenes can be activated by () → results in elevated expression
gene amplification
amplification of the oncogene () (encodes RTK) is related to rapid growth of breast and ovarian tumors
erbB-2
the main purpose of oncogene protein production is to (1), as well as to (2)
- promote cell proliferation and survival
- prevent programmed cell death
functions of oncogene products include:
- activation of the ERK pathway
- transcriptional activation
- increasing cell proliferation
- inhibition of cell differentiation
- promotion of cell survival
all the components of ERK pathway () can serve as oncogene proteins
- polypeptide growth factors
- growth factor receptors
- intracellular signaling proteins
- transcription factors
give an overview of how the receptor for platelet-derived growth factor (PDGFR) can act as an oncogenic product (due to chromosome translocation)
- translocation results in PDGFRs with amino terminal sequences of the transcription factor Tel
- PDGFR+Tel oncogene proteins have a dimerization domain that constitutively keeps the receptor active → even without PDGF stimulation, pathway is activated and cell continuously proliferates
transcription of the () is induced by phosphorylation of Elk-1 by the ERK pathway
fos proto-oncogene
explain how transcription of the fos proto-oncogene can lead to tumor formation
- fos encodes for Fos, which dimerizes with Jun to form the AP-1 transcription factor
- AP-1 transcription factor then activates transcription of cyclin D1 → promotes cell proliferation
Fos dimerizes with Jun to form ()
AP-1 transcription factor
() were identified as oncogenes in mouse breast cancers
Wnt proteins
explain how Wnt proteins serve as oncogenes
- Wnt signaling pathway triggers degradation of beta-catenin
- mutations convert beta-catenin (downstream target of the Wnt pathway) to an oncogene called CTNNB1
- CTNNB1 is more stabilized than beta-catenin → it is not degraded and can cause unregulated transcription of the c-myc oncogene as well as cycD1 (in coordination with the transcription factor Tcf)
mutations convert beta-catenin (downstream target of the Wnt pathway) to an oncogene called ()
CTNNB1
CTNNB1 is more stablized that beta-catenin → it is not degraded and can cause unregulated transcription of the c-myc oncogene as well as cycD1 in coordination with the transcription factor ()
Tcf
gene encoding cycD1 (it is a proto-oncogene) can become an oncogene called () by chromosome translocation or gene amplification
CCND1
catalytic partners of cycD1: () are also activated as oncogenes by point mutations, gene amplification, and chromosome translocation
Cdk4 and Cdk6
mutated form of thyroid hormone receptor that can lead to maintaining leukemic cells in an actively proliferating state
ErbA
mutated form of retinoic acid receptor that can lead to maintaining leukemic cells in an actively proliferating state due to blocking of cell differentiation
PML/RAR(alpha)
acute promyelocytic leukemia can be treated with high doses of () → induces differentiation because effect of PML/RAR(alpha) oncogene is overridden
retinoic acid
failure of cancer cells to () is a critical factor in tumor development
undergo programmed cell death
PI 3-kinase and Akt act as oncogenes if they () → preventing cell death
constitutively keep the pathway active
elevated expression of the antiapoptotic protein Bcl-2 also causes to serve as an oncogene by ()
blocking apoptosis
