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Summary Molecular Cell Biology (B_MOLECULBIO)
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A summary of the lectures and literature for molecular cell biology of the research master human movement sciences at the VU
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Molecular BiologyLecture 1 – introduction
Chapter 5 and article Alessi-wolken
Fibrodysplasia ossificans progressiva:
Fibrodysplasia
o Abnormal development of fibrous connective tissue
Ossificans
o Has to do with bone (Os..)
Progressiva
o A progressive disease
FOP:
Ectopic bone formation, toe deformities
Early in life with episodic, yet progressive and cumulative, heterotopic ossifications (HO) of
ligaments, tendons, and a subset of major skeletal muscles.
o Evident at birth or shortly thereafter
o Inflammation is a common trigger for HO
It affects 1:2 million people only 9 cases in The Netherlands
A BMP receptor type 1 is mutated ACVR! dominant gain of function
o Activin A Receptor Type 1 is mutated
o Disease probably ligand dependent and involve ligands that not only activate ACVR1
but also regulated by inflammation
Mysterious what triggers the progression of the disease molecules of importance are not
known
o Activin might trigger the mutated ACVR1
Gives rise to bone formation
Antibodies against ACVR1 inhibit disease progression in a mouse model
To date no cure, no medicine
Difficult to address, while patient material is scarce
Alessi-Wolken et al.,
Developed a conditional-on knock-in mouse model
FOP-causing ACVR1 variants drive HO in FOP by perceiving their own natural antagonist –
Activin A – as an agonist
Inhibition of Activin A using an anti-Activin A mAB has been effective irrespective of whether
heterotopic ossification was ‘spontaneous’
showed that activation of BMP signaling alone was not capable of inducing the formation of
heterotopic bone in skeletal muscles – injury or some other type of tissue damage was also
required
Together with the finding that Activin A is the main physiologic driver of HO in FOP (via mutant
ACVR1), these results effectively confirmed our initial hypothesis that the process of HO in FOP is
ligand-dependent. Furthermore, also in line with our original hypothesis, HO in FOP involves a ligand
that not only activates ACVR1[R206H] (and all the other FOPcausing variants of ACVR1) but it is also
regulated by inflammation, and recognized by tissue-resident progenitor cells that can give rise to
heterotopic bone via an endochondral process.
Molecular cell biology studies cellular processes at the DNA/RNA level.
A cell differs in morphology, function, proteins and gene expression.
1
,All cells contain DNA:
Consists of two strands, genome per cell = 2 meter!
Millions of nucleotides. G, A, T and C
Functional units called genes (+/- 25.000)
2 copies of each gene
Each gene is a specific and unique sequence of G, A, T and C’s
Each gene encodes one protein
When to use molecular biology?
What is the molecular basis of differences between cells?
How do cells respond to stimuli?
o Enhanced or repressed expression of certain genes
RT_PCR
Microarray
Which genes are important for the function of the cell?
o Manipulation with: transfection (more expression) or siRNA
all molecular biological techniques make use of unique sequences can be manipulated with
complimentary molecules molecular biology makes use of enzymes necessary for synthesis of
RNA/DNA
Transcription: The DNA double helix is spliced and then one of the strands is transcribed bij RNA
polymerase RNA
Translation: the RNA is translated to a protein by a ribosome tRNA binds with polypeptide
couples to the right sequence of nucleotides all the parts coupled protein
Between the to complementary nucleotides form the two DNA strains there is a hydrogen bond.
Between G and C there are 3 and between A and T there are 2.
2
, Watson and Crick came up with the double helix model, but they were inspired by Rosalyn Franklin
and her X-ray structure of DNA!
The nucleic acids are oriented from the 5’ end to the 3’ end.
Interactive on DNA replication:
Each cell contains 2 meter of DNA how to make DNA replication effective?
Divided over 46 chromosomes
Each chromosome contains multiple origins of replication
Interphase: when chromosomes are duplicated, mitosis: when they are distributed to the two
daughter nuclei
Should know for exam!
Telomeres: at each of the two ends of a
chromosome, contain repeated nucleotide
sequences that are required for the ends of the
chromosomes to be replicated.
The centromere part is not actively transcribed,
it allows duplicated chromosomes to be
separated during the M phase.
Nucleolus: where the parts of the different
chromosomes carrying genes that encode
ribosomal RNAs cluster together.
3
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