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Wednesday, August 20, 2008

The Calcium Gate Hypothesis of Cancer

In 1978 I was finishing my Masters in Public Health at the University of Michigan School of Public Health. I had fallen under the spell of Dr. Bruce Chin who was enthusiastically studying the mechanisms of carcinogenesis. I took his advanced class in understanding the cellular mechanisms of cancer three times. During this time, I also developed my ideas that there must be a crucial switch that turns this cancerous process on and off and that the most likely candidate for this switch was an as yet unknown calcium gate that could be controlled by phosphorylation and dephosphorylation. This gate would be analogous to the then known cardiac gate controlled by phospholamban, which was discovered by Dr. Madeleine Kirchberger at the Mount Sinai School of Medicine in New York. I wrote this hypothesis into a paper that I submitted to the Journal of Theoretical Biology, but it wasn’t accepted for publication.

Ironically I came to New York in 1979 and later found myself working in Dr. Kirchberger’s lab on a project to isolate and purify phospholamban, but phopholamban is a membrane bound protein that was more difficult to purify than we initially thought and since I couldn’t reproduce my initial results, I had to drop this project and start a new project for a Ph.D. thesis. However, I very much admired the rigorous research integrity and intensity of Dr. Kirchberger’s lab and I learned a great deal about phospholamban and calcium signaling in the heart. I was still convinced that there must be a connection between the uncontrolled cell division in cancer cells and the control of the calcium gate in normal cells. I discussed this idea with many scientists because I wanted to find someone who was working in this area, but it still needed much more development to become a mainstream idea.

Years passed and I periodically scanned the literature to see if there had been more thought about the calcium gate hypothesis and cancer. The cancer field seemed to take off in the direction of a balance between kinase and phosphatase control of the cell’s metabolic machinery. This seemed to be promising since I had thought that the calcium gate would be controlled by the kinase and phosphatase molecules. The calcium field seemed to have its own direction and developed into an important field of research focusing on the myriad number of enzymes and kinases controlled by calcium signals. However, there didn’t appear to be a direct connection made between a particular kinase/phosphatase pair that were crucial in controlling a start/stop point in cell division.

This has now begun to change and suggests a redox sensitive switch -see:

http://www.ncbi.nlm.nih.gov/pubmed/18377233?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/17168752?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/18544350?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18372105?ordinalpos=20&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18671159?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18466777?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


Is it just coincidence that oncogenes and calcium control genes are near each other? The following list contains searches for oncogenes that happen to appear near to calcium control genes (clicking on the links give GOOGLE searches for the oncogene and the calcium gene and cancer):


27
Hs
ABL2
v-abl Abelson murine leukemia viral
oncogene homolog 2 (arg, Abelson-related
gene)
1q24-q25


777
Hs
CACNA1E
calcium channel, voltage-dependent,
alpha 1E subunit
1q25-q31

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%221q24-q25%22+1q25-q31&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



208
Hs
AKT2
v-akt murine thymoma viral oncogene
homolog 2
19q13.1-q13.2

773
Hs
CACNA1A
calcium channel, voltage-dependent,P/Q type, alpha 1A subunit
19p13.1-p13.2


51476
Hs
CABP3
calcium binding protein 3
19q13.33

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2219q13.1-q13.2+%22+19q13.33&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



867
Hs
CBL
Cas-Br-M (murine) ecotropic retroviral
transforming sequence
11q23.3

57010
Hs
CABP4
calcium binding protein 4
11



781
Hs
CACNA2D1
calcium channel, voltage-dependent,
alpha 2/delta subunit 1
7q21-q22
673
Hs
BRAF
v-raf murine sarcoma viral oncogene
homolog B1
7q34

674
HsBRAFP
v-raf murine sarcoma viral oncogene
homolog B1 pseudogene
7q34

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%227q34+%22+7q21-q22&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


12298
Mm
Cacnb4
calcium channel beta 4 subunit
2 33.9 cM
12170
Mm
Bmyc
brain expressed myelocytomatosis
oncogene
2


782
Hs
CACNB1
calcium channel, voltage-dependent,
beta 1 subunit
17q21-q22
1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3



54245
Rn
Crk
v-crk avian sarcoma virus CT10 oncogene
homolog
10
783
Hs
CACNB2calcium channel, voltage-dependent,
beta 2 subunit
10p12

12296
Mm
Cacnb2
calcium channel beta 2 subunit
2 14.5 cM

12298
Mm
Cacnb4
calcium channel beta 4 subunit
2 33.9 cM

12170
Mm
Bmyc
brain expressed myelocytomatosis
oncogene
2



773
Hs
CACNA1A
calcium channel, voltage-dependent,
P/Q type, alpha 1A subunit
19p13.1-p13.2

1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3+%22+19p13.1-p13.2&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



775
HsCACNA1C
calcium channel, voltage-dependent, L
type, alpha 1C subunit
12p13.3
1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3+%22+12p13.3&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

778
Hs
CACNA1F
calcium channel, voltage-dependent,
alpha 1F subunit
Xp11.23
867
Hs
CBL
Cas-Br-M (murine) ecotropic retroviral
transforming sequence
11q23.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2211q23.3%22+Xp11.23&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



8911
Hs
CACNA1I
calcium channel, voltage-dependent,
alpha 1I subunit
22q13.1

1399
Hs
CRKL
v-crk avian sarcoma virus CT10 oncogene
homolog-like
22q11.21

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2222q11.21%22+22q13.1&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


782
Hs
CACNB1
calcium channel, voltage-dependent,
beta 1 subunit
17q21-q22

1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3%22+17q21-q22&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


12295
Mm
Cacnb1
calcium channel beta 1 subunit
11 58.0 cM
12928
Mm
Crko
avian sarcoma virus CT10 (v-crk)
oncogene homolog
11 44.15 cM

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2211+44.15+cM%22+11+58.0+cM&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


1436
Hs
CSF1R
colony stimulating factor 1 receptor,
formerly McDonough feline sarcoma viral
(v-fms) oncogene homolog
5q33-q35
Links309
Hs
ANXA6
annexin A6
5q32-q34



776
Hs
CACNA1D
calcium channel, voltage-dependent, L
type, alpha 1D subunit
3p14.3

1894
Hs
ECT2
epithelial cell transforming sequence 2
oncogene
3q26.1-q26.2

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%223q26.1-q26.2%22+3p14.3&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

12291
Mm
Cacna1g
calcium channel, voltage-dependent, T
type, alpha 1G subunit
11
13649
Mm
Egfr
epidermal growth factor receptor
11 9.0 cM


12295
Mm
Cacnb1
calcium channel beta 1 subunit
11 58.0 cM

13649Mm
Egfr
epidermal growth factor receptor
11 9.0 cM



24329
Rn
Egfr
Epidermal growth factor receptor, formerly
avian erythroblastic leukemia viral (v-erbB)
oncogene homolog (Erbb1)
14

12289
Mm
Cacna1d
calcium channel, voltage-dependent, L
type, alpha 1D subunit
14 8.0 cM

54234
Rn
Cacna1e
calcium channel, voltage-dependent, L
type, alpha 1E subunit



2002
Hs
ELK1
ELK1, member of ETS oncogene family
Xp11.2

778
Hs
CACNA1F
calcium channel, voltage-dependent,
alpha 1F subunit
Xp11.23

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=Xp11.2+Xp11.23&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

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