Lecture 8 Flashcards
TGFb prevents phosphorylation of
Rb-blocks cell cycle progression
TGFb prevents phosphorylation of Rb-blocks cell cycle progression
- Major Growth inhibitory signal forNormal Cells
- Counteracts actions of MYC (MYC is growth promoting).
– MYC represses expression of both p15 and p21. - In normal cells TGFb reduces c-MYC expression-Smad3 and E2F4/5 and
p107 shut down c-MYC expression. In breast cancer this TGFb-mediated
repression of MYC is LOST. - TGFb signalling-Smad2/3 associate with Smad4-heterotrimeric complex
moves to nucleus-collaborates with Miz-1 (TF) to induce expression of p21
and p15 (CDKIs). In cancers where MYC is overexpressed these CDKIs are
repressed (oncogenic MYC wins over TGFb signals). - Many cancers evade TGFb growth inhibition (eg half of pancreatic cancers
have mutant inactivated Smad4 proteins)
Other Controls
Damaged DNA…role of p53.
Another feedback mechanism prevents division in the
presence of damaged DNA (halt at G1, G2, or M)
p53 protein involved
p53 gene mutation is common in many transformed
cells.
Akt
- Akt, a serine/threonine kinase is activated downstream of Growth factor Receptors
- Functions include inhibition of CDK Inhibitors and promoting progression of cell
cycle by blocking the actions of GSK3b. (GLYCOGEN SYNTHASE KINASE 3b) - Also blocks the actions of a pro-apoptotic protein, Bad, (later lecture on Apoptosis)
and promotes cell growth
Growth Factors (eg EGF) that signal through Akt lead to the
inhibition
of the actions of the CDKIs p21 and p27. (A) Akt phosphorylates p21 and
p27, which leads to their translocation from the nucleus to the
cytoplasm-degraded by proteosome
Akt also phosphorylates
GSK3b leading to the inactivation of GSK3btargets of GSK3b include MYC and CyclinD1 (GSK3b inhibitory action on
both MYC and CyclinD1)
In cancer
“Hallmark” features of Cancer is Autonomous cell
division (ie no longer dependent on positive and
negative growth factors)
* The PI3K-AKT and RAS-RAF-MEK-ERK pathways are
thought to play a central role in transmitting oncogenic
signals.
* So Is the expression levels altered or the activity altered
(eg if a kinase for example) of proteins such as Akt, RAS
or MYC in Cancer-are they different from normal cells?
* Yes Eg in BREAST CANCER=
* RAS and Akt are abnormally activated and MYC
amplification is a frequent event in breast tumors
Increased Akt Activity is a frequent event in
Cancer including Breast cancer
TUMOR GRADE LINKED WITH HIGHER
pAKT EXPRESSION
AND REDUCED NUCLEAR P27