Biology 457 & 557 - Week 11
last ex: of linkage between stimulation of a cell-surface receptor to gene expression
in this case, the ligand is a cytokine (secreted, small proteins that bind to cell-surface receptors on certain cells to stimulate proliferation) known as
interferon is produced and secreted by animal cells
binding of these hormones by other surrounding cells inhibits their growth and induces the synthesis of
by studying the response of cultured mammalian cells to the different interferons, new classes of protein kinases called the
these factors make up the Jak/Stat signaling pathway
to start, the interferon receptors do not have
rather, the cytosolic domain is phosphorylated
Jak 1 & 2 phosphorylate tyrosine residues on cytosolic Stats
Stats can form stable homodimers (1a + 1a) or heterodimers (1a + 2) that are translocated to the nucleus
Stat dimers are actually transcription factors that direct gene transcription and there is specificity to what genes they control
ex: activated INFa receptors yield Stat1a-Stat2 heterodimers
ex: binding of IFNg to its receptor induces transcription of genes containing a response element called
lastly, it has been determined that binding of other ligands to other types of cell-surface receptors also may trigger
ex: binding of EGF to a receptor protein kinase (receptor with protein kinase domain) causes the phosphorylation of
this finding is important because it shows that multiple pathways can lead to
so Stats are transcription factors….are there others and can they be stimulated by multiple pathways?
other types include:
1) CREB proteins
2) serum response factors, what are these?
it has been determined that addition of growth factors (EGF, PDGF) to quiescent cultured mammalian cells in G0 causes a rapid
these are the early response genes
one important early response gene is this c-fos
this factor, along with other proteins, induces expression of many genes
of interest is the fact that induction of c-fos can be mediated by several different intracellular signaling pathways
how can all three activate the same gene?
nuclear transcription factors:
these oncogenes exert direct effects on transcription rates by
ex’s: the family of Fos and Jun proteins are known oncoproteins which activate
these proteins are characterized by a DNA binding domain and a
hydrophobic leucine zipper domain
part of the AP-1 (activator protein 1) transcription factor complex –
AP-1 activity is enhanced by either increased translation of Fos and Jun
these genes are differentially expressed during development which
suggests that these proteins have distinct functions
found that Jun can bind to the cAMP response element and can dimerize
the oncogenic form of Jun has lost a portion of the N-terminal region that
is thought to facilitate or stabilize the interaction with
in Fos, there is a deletion in the C-terminal region and it can still dimerize
with Jun, but this dimer does not activate AP-1 promoters
ex: mention a few characteristics of another presumed transcription factor Myc
and its role in
they form heterodimers with the nuclear protein Max and can bind to enhancer
elements
Max can also homodimerize and form heterodimers with the protein
the Max-Max and Mad-Max dimers bind to the same enhancers as
thus, Max stimulates gene expression when complexed with Myc
in the absence of appropriate growth factors, Myc can associate with Max and
induce
how can this become oncogenic? (in the case of B cell lymphomas)
there is a genetic rearrangement (translocation) that places the myc gene
places the myc gene under the control of
in this case, the Myc protein is deregulated (always on) and get ectopic
expression
overexpression of myc disturbs the fine balance of transcriptional regulators by
elevating the relative concentration of
overexpression found in some cases of
one last example of a proto-oncogenic transcription factor that can be altered and form an oncogenic protein
ex: TAL1 gene (first identified in T cell acute leukemia 1) is a transcription factor
is a member of the basic helix-loop-helix (bHLH) protein family (basic region
mediates DNA binding and the HLH motifs mediates protein interactions) and
can form heterodimers
when TAL1 associates with E2A proteins, the heterodimer binds to the
expressed in developing brain, normal bone marrow and mast cells, endothelial
cells
how then does it get expressed in T cells as mentioned above?
activated by certain TAL1 rearrangements
this ectopic expression turns on expression of genes not normally under the control of this transcription factor
is expression of TAL1 alone sufficient to cause tumorigenesis?
actually have found that TAL1
LMO1 & 2 are also activated by chromosomal rearrangements
this finding suggests that TAL1 requires LMO1 for inappropriate activation of downstream genes