Lecture 9: MYC Flashcards
MYC
a key oncogene
MYC-a key oncogene
Connects to Cell Growth, Proliferation and Apoptosis-HOW?
MYC is overexpressed in a wide range of cancers including
Breast, Colon, Cervical, Lung, melanomas, glioblastomas,
lymphoma
* MYC regulates 1000’s of genes, accounts for 15-20% of all
genes
* MYC (8q24) gene amplification is frequently detected (15%
of cancers), protein overexpression is detected in 40% of
breast cancer (additional mechanisms of MYC deregulation
involved) or MYC is translocated in other cancers (Burkitt’s
lymphoma
* MYC protein is subject to PTM including phosphorylation,
acetylation and ubiquitinylation. Affects interaction
with other proteins and transcriptional activity.
c-myc is translocated in
Burkitt’s Lymphoma
Burkitt’s Lymphoma =
aggressive B cell malignancy associated with EBV infection
(Type of NHL)
Translocation of c-myc to Ig Heavy chain locus places MYC gene under highly active
transcriptional regulators
Remember c-myc translocation is not sufficient for malignancy!
Burkitt’s Lymphoma:
Uganda 5/ 105 cases /year;
US : 1/106/year cases/year
Despite similar EBV carriage, Malaria infection linkage
c-myc gene Human
Ch8q24:
c-Myc protein, short half-life, subject to
post-translational modifications
Belong to a large family of bHLH transcription factors (basic DNA binding domain
followed by amino acid sequences forming an a-helix, a loop and a second a-helix.
Full activity needs to d
dimerise with partner MAX (basic HLH zipper protein-MAX
levels quite constant in cells) at LZ region, and phosphorylation in TAD. Translocates
to nucleus bind E-box motif (sequence CACGTG) which are found in the promoters
of target genes.
Transcriptional targets of MYC/MAX include
E2F1, E2F2, E2F3
transcription factors, Cyclin D2, CDK4, CUL1 (component of SCFSkp2
E3 ligase).
MYC-MAX heterodimer binds to
E-box sequence CACGTG of target
genes (or with noncanonical sequences) to regulate gene transcription
Multiple coactivator complexes such as TRRAP are involved. TRRAP
(transformation/transcription domain associated protein) is part of a
complex that contains histone acetyl transferase (HAT) activity.
Regulation of MYC
Phosphorylation at Thr58 targets MYC for
degradation-mutations
at or near this residue common in cancer.
GSK3 is a serine/threonine kinase, ubiquitously
expressed and in resting cells is constitutively
active, and inactivated by mitogenic signals eg
kinase AKT (inactivates GSK3 through
phosphorylation). MYC is stabilised with
phosphorylation at Ser62 by MAPK, a Ras
downstream effector
MYC short protein half-life 15-30min
Mitogenic signals lead to higher MYC levels
MYC is regulated by Multiple Signalling pathways.
Ras, Wnt, Notch, EGFR pathways positively regulate MYC
expression or stability.
TGFb and BRCA1 inhibit MYC gene expression and activity,
respectively (but are mutated frequently in cancer) .
MYC promotes cell cycle progression.
MYC/MAX regulates CyclinD2 (CCND2) and CDK4 expression-CyclinD/CDK4
sequesters p27 (aka KIP1). MYC is involved in p27 degradation (p27Kip1). MYC
transcriptionally regulates CUL1 (component of SCFSkp2 E3 ligase).
CAK then phosphorylates CDK2Vleading to active CyclinE/CDK2-required for Rb
hyperphosphorylation and E2F release. Myc is able to induce expression of
genes encoding E2F1, E2F2, E2F3 transcription factors
MYC binds to MIZ-1 (Transcription Factor) and leads——————————-MYC/MAX also positively regulates
to reduced
p15 and p21 (CDKIs) expression.
s the degradation of the CDKI
p27.
Myc and Metabolism
Increase in Metabolic activity
- Cancer cells use altered metabolic program; increased glucose uptake and process it largely by aerobic glycolysis
(Warburg effect). - Altered metabolic program provides substrates and energy for tumour growth-accumulates key intermediates
nucleotides, amino acids and lipids needed to support growth and cell division - In cancers MYC is involved in this altered metabolic program. MYC regulates – lactate dehydrogenase A (LDHA), glucose
transporter (GLUT1), hexokinase 2 (HK2), phosphofructokinase (PFKM), and enolase 1 (ENO1) - MYC is involved in Ribosome biogenesis-global increase in protein synthesis
Myc is involved in hTERT expression-Telomerase
- Activity detected in 90% human tumour cell samples
- MYC activates Telomerase by inducing expression of its catalytic subunit, telomerase reverse transcriptase (TERT).
- Telomerase activity is largely absent from somatic cells in vivo and from normal human cells in culture (Counter et al. 1992).
- As cells proliferate, telomeric repeats are progressively lost as a result of incomplete replication of chromosome ends during each
division cycle (Watson 1972; Olovnikov 1973; Harley et al. 1990; Hastie et al. 1990). - Telomere shortening has been proposed as the mitotic clock that marks the progress of a cell toward the end of its replicative life
span. - According to this model, erosion of chromosome ends triggers cellular senescence (Harley et al. 1990; for review, see Harley 1991).
- Some cells (eg STEM cells, Cancer cells) express telomerase which can increase the length of telomeres adds repeat sequence -
TTAGGG .
