Lecture 5 (myc) Flashcards
What is MYC?
Myc is a family of regulator genes and proto-oncogenes that encode for transcription factors
MYC is overexpressed in what cancers:
Breast, Colon, Cervical, Lung, melanomas, glioblastomas, lymphoma
How does post-translational modifications affect MYC.
It affects interaction with other proteins and transcriptional activity.
What is Burkitt’s Lymphoma:
It is an aggressive B cell malignancy (cancer) associated with EBV infection.
How is Burkitt’s Lymphoma caused:
Translocation of c-myc to Ig Heavy chain locus
(Which is a stronger promoter so MYC expression is increased)
Structure of MYC
-Has a basic DNA binding domain followed by amino acid sequences forming an a-helix, a loop and a second a-helix.
-bHLH leucine zipper transcription factor.
How can Myc become fully activated
By dimerizing with MAX at the leucine zipper region and phosphorylation at the transactivation domain (TAD)
MYC/MAX binds to?
To the E-box sequence CACGTG of target genes to regulate gene transcription
Binding of MYC/MAX to the EBOX leads to activation of what genes:
-E2F1, E2F2, E2F3
-Transcription factors, Cyclin D2 and CDK4
-CUL1
EBOX stands for?
Enhancer Box
How can MYC be targeted for degradation
Phosphorylation at Thr58 targets.
Therefore mutations at or near this residue are common in cancer.
What is GSK3
GSK3 is a serine/threonine kinase, ubiquitously expressed and in resting cells is constitutively active, and inactivated by mitogenic signals.
What is TRRAP
-TRRAP (transformation/transcription domain associated protein) is part of a complex that contains histone acetyl transferase (HAT) activity.
-TRRAP is involved in the MYC/MAX binding to EBOX.
How can MYC be stabilized?
By phosphorylation at Ser62 by MAPK, a Ras downstream effector.
MYC’s half life:
It is a short half life of 15-30mins.
MYC levels are high when
There is an increase in mitogenic signals.
Pathways that positively regulate MYC expression
Ras, Wnt, Notch, EGFR pathways
Pathways that inhibit MYC expression
TGFb and BRCA1
How MYC promotes cell cycle progression:
-Regulates cyclin D2 and CDK4 expression which are involved in the transition through G1 phase to S phase.
-Degrades CDKIs p27 and p21.
-Transcriptionally regulates CUL2.
-Phosphorylation of CDK2 by CAK allows active cyclin E/CDK2 to hyperphosphorylated RB which causes E2F to be released.
-Therefore, MYC promotes cell cycle progression by ultimately leading to expression of genes encoding E2F1, E2F2, E2F3 transcription factors which are used in S phase for DNA replication.
How does MYC lead to reduced p15 and p21 expression
By binding to the transcription factor MIZ.
MYC/MAX do what to p27
They positively regulate p27 degredation.
What is the Warburg effect
When tumor cells use increased glucose uptake to grow.
How does MYC activates Telomerase
By inducing expression of its catalytic subunit, telomerase reverse transcriptase (TERT).
How does MYC positively regulates Angiogenesis
By upregulating VEGF expression
MYC downregulates E-cadherin expression which leads to
To increased cell motility (invasiveness)
