Biology 457 & 557 - Week 9
the family of transcription factors that regulate transcription of these genes is called
1) RB protein –
2) p107 –
RB protein – its ability to inhibit the activity of E2F
ex: cultured cells derived from a tumor defective in both Rb alleles
if transfect these cells with a vector carrying Rb gene, what do you think
will happen?
bigger picture - the mammalian G1 Cdk-cyclin complexes and Ckd2-cyclin A can
in normal cycling cells, RB is
serious genetic damage can occur if cells progress to the next phase of the cell cycle
1): induce S phase cells to enter mitosis (done by fusing these cells to cells
in mitosis) because the MPF (maturation promoting factor – mentioned this
when discussing oocyte maturation; initiation of mitosis in all euk. cells)
present in the mitotic cell forces the chromosomes of the S phase cell to
prematurely condense, which causes the chromosomes to fragment
2): attachment of microtubules (spindle fibers) to kinetochores (centromeres)
during metaphase, if not done correctly can result in
3): cell can’t enter mitosis until all DNA is replicated
4): defects in the assembly of mitotic spindle prevents exit from mitosis
have found that a checkpoint control somehow senses when the spindle
has not formed properly
MPF activity remains high, chromosomes remain condensed
this was described when yeast cells were treated with a microtubule-
depolymerizing drug called
at low conc. of benomyl, yeast cells took longer to assemble mitotic
spindle and attach kinetochores to microtubules (delay anaphase)
in contrast, mutants defective in this cell cycle checkpoint proceed through
anaphase before assembly of spindle
thought that at least one of the genes important to this is a
5): DNA damage prevents entry into S phase and mitosis
if a cell is damaged by irradiation with UV light or by chemical treatment,
the cell arrests in G1
ex: G1 – the p53 tumor suppressor gene functions in the checkpoint
p53 codes for a transcription factor
cells are arrested in G1 until DNA damage is repaired
in a high % of human cancers
seen that cell cycle regulation is very important to induction of a cancerous cell……when lose control then the cell
think back to the lecture on cultured cells and I mentioned transformation as a mechanism whereby growth characteristics of cultured cells are altered (by viruses, chemicals, radiation) and they develop a tumor-forming capacity
what other events can trigger transformation?
expression of one or a few
oncology
ONCOGENES
characteristics:
of the many known oncogenes, almost all are derivatives of
these cellular counterparts are called
oncoproteins are then the protein products
a) some oncoproteins are mutant forms of the protein product of
b) sometimes the protein products of both the oncogene and proto-oncogene
are the same, but
in these cases, the mutation creating the oncogene changes
a proto-oncogene and its related oncogene are designated with a 3 letter code
many oncogenes were first identified through the study of cancer induced by
the retroviruses were found to contain or carry oncogenes
however, since not all retroviruses carry oncogenes, where did such genes originate?
are they viral in origin?
or might they represent genes captured by the virus from host animal cells?
the identification of the oncogene has frequently led to discovery of the corresponding
the oncogene in a virus is denoted with a v prefix (ex: v-src)
oncogenes have also been identified by transfection
how many oncogenes have been discovered?
5 types of proteins, depending on how they participate in control of cell growth
oncogenes can code for :
1)
2)
3)
4)
5)
growth factors:
mentioned before that cells in culture can be induced to grow by addition of
specific growth factors ex: EGF -
ex: PDGF -
these ligands serve as
it is a way for cells to
specific signals can produce a response in some cell types
ex: EGF stimulates growth
oncogenes rarely arise from genes
really only one naturally occurring growth factor oncogene
ex: sis –
growth factor receptors:
a receptor binds a specific factor and then the receptor, recognizing it has bound this factor, will send a
how do growth factor receptors work?
these receptors have
transmit the growth signal by:
1) autophosphorylating
2) phophorylating
normally, inactive receptors exist in an inactive
when bound by a growth factor, these receptors
the activated receptor autophosphorylates additional
these phosphorylated sites serve to recruit cytoplasmic targets of the
src gene 2
how then do these receptors become oncogenic?
1) they are mutated in such a way as to keep the
2) gene amplification
in most cases, much of the extracellular ligand-binding domain is deleted and the
altered receptor has lost ligand control
ex: c-erb-B gene
in another case, there is a single point mutation that results in an amino acid
substitution
ex: neu oncogene
suggested that this substitution induces dimerization of the oncogenic Neu protein
or, the neu gene has been amplified and overexpressed
this is found in human mammary carcinomas and ovarian cancers
also, it has been determined that amplification of the c-erb-B gene and subsequent
overexpression of the EGF receptor is common in
a cell containing a constitutively active oncogenic receptor grows
independently
such mutant receptors can induce a spectrum of neoplasia