6. Heat Shock Proteins (HSPs)
Categorized, according to their molecular weights, into
various families
• HSP 90
• HSP 70
• HSP 60
• HSP 40
• Small HSPs or α crystalline proteins
7. Major functions
Family Function
HSP90 Regulatory interactions with signalling proteins, stabilization of
misfolded proteins
HSP70 Protein folding, membrane transport of proteins, auto regulation if
heat shock response, anti-apoptotic
HSP60 Protein folding (limited to cytoplasm)
HSP40 Protein folding, co-chaperon for HSP70
Small
HSPs
Stabilization of misfolded proteins, eye lens structural proteins
8.
9. HSP 90
In cancer cells, enhances growth, supresses senescence,
provides resistance to stress induced apoptosis (i.e. confers
protection against apoptosis due to cytotoxic drugs and
radiation therapy)
11. Efungumab
• Fungi, in stress, produce HSP90 which confers resistance.
• Efungumab, a HSP90 inhibitor, was one such anti-fungal to
be introduced for the treatment of invasive candidiasis.
12. HSP 70
• In cancer cells, enhances growth, supresses senescence,
provides resistance to stress induced apoptosis (i.e. confers
protection against apoptosis due to cytotoxic drugs and
radiation therapy)
• Triptolide
• Used in pancreatic cancer
• Induces apoptosis by inhibiting HSP70
• BIIB021, a HSP90 inhibitor, enhances activity of Triptolide
13. HSP 70
• In sympathetic neurons,
• HSP 72 – inhibits degradation of Tau protein, heat shock inducible.
• HSC 70 - promotes degradation of Tau protein.
• Methylene blue – inhibits ATPase activity of HSP70 (72)
• Reduces Tau polyglutamine formation
• Improves cognition in Alzheimer’s disease
• Phase IIb
14. HSP 60
• In the mitochondira, replication and transcription of DNA,
pro – survival.
• In the cytosol, it forms complexes and inhibits maturation
and activation of Caspase 3 – Anti apoptotic
• Epolacteane tertiary butyl ester (ETB) – prevents binding of
HSP60 with mtf1, thereby preventing mitochondrial
transcription - Apoptosis
15. HSP 60
• Surface and extracellular
• Stimulates immune response
• Bortezomib – increases expression of HSP 60 on
malignant cells and thus enhances immune response
against tumour cells.
16. HSP 40
• Excess HSP40-HSP70 complex leads to accumulation of
polyglutamine proteins Neurodegenerative diseases.
• Quercetin (Pre-clinical, Inhibits HSP 40 and 27)
17. HSP 27 (HSP β1)
• Anti-oxidant (increases glutathione levels and decreases
iron levels)
• Anti-apoptotic in response to chemicals (inhibits liberation
of cytochrome c from mitochondria preventing
proteolysis)
• Apatorsen (Phase II)
18. HSP 27
As a diagnostic tool
• Increased in – Renal injury and fibrosis, Cancers of
breast, lung, liver, prostate, rectal, osteosarcoma,
leukemia, cerebral and cardiac ischemia
• Reduced in – oesophageal cancer
• Anti-HSP27 IgA – Gyneacological malignancies
19. Conclusion
• In todays date and time, emphasis is laid on cancer
chemotherapy and ‘n’ number of drugs are under clinical
trails for the same.
• Sure, these will be a boon to the health care system in the
near future, however diverting focus on neurodegenerative
disorders would be a welcome change.
• Similarly, bacteria and fungi also produce HSPs when under
stress, exploiting this area will help cope with the stress of
‘antibiotic resistance’.
Editor's Notes
Cancers and neurodegenerative diseases
Parkinsons - Lewy bodies
Stress – change in temp, pH, oxidizing agents, heavy metals, poisonous gases.
HSP – Stabilize proteins, provide stress free environment
60 - (Chaperonin)
HSP100 Stress tolerance, thermo-tolerance, protein disaggregation
Cancer and neurodegenerative diseases
Growth – Erb2, Met
Senescence – binds to telomerase
With Imatinib (CML – reduction in Bcr-abl) bortezomib, arsenic trioxide, doxorubicin
All under phase 1 for various cancers
Radicilol – Inhibits hsp90-client protein complex signalling.