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发信人: justacode (Hi), 信区: Biology
标 题: Call for MCBJC pathway, Mar. 31
发信站: The unknown SPACE (Mon Mar 31 10:52:51 2003) WWW-POST
Science (2003) 299: 223-226
“These caspases cleave many intracellular substrates, ultimately leading to
cell death.”
Why pathway study is important?
"it's importmant for sure. without knowing the central death pathway, how
would people study the regulation of the pathway? Usually signalling pathway
are
conserved between species, so if we know the pathway, we can manipulate
apoptosis. if we want cancer cell to die, we stimulate the death pathway. if
we want degenerating neurons survive, we can prevent the apoptosis to
happen."
--
※ 修改:·justacode 於 Mar 31 10:52:51 修改本文·[FROM: 140.251.]
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 140.251.]
发信人: assasin (冷血---何时能被加热？), 信区: Biology
标 题: Apoptosis---Re: Call for MCBJC dicussion
发信站: The unknown SPACE (Tue Apr 1 02:13:55 2003) WWW-POST
This paper published by Wang Xiaodong's lab is a real landmark paper, again.
It combines chemical screening with beautiful biochemistry to set up an assay
for identifying new factors in apoptotic pathway. They identified 4 factors
and characterized one's function. I hope people read this paper and think
about the logic and beauty of their way of asking, addressing, explaining
scientific questions. I predict that 2 or 3 CNS papers will come out the wang
lab following this paper.
【 在 justacode (Hi) 的大作中提到: 】
: Science (2003) 299: 223-226
: “These caspases cleave many intracellular substrates, ultimately leading to
: cell death.”
:
:
: Why pathway study is important?
:
: "it's importmant for sure. without knowing the central death pathway, how
: would people study the regulation of the pathway? Usually signalling
pathway
: are
: conserved between species, so if we know the pathway, we can manipulate
: apoptosis. if we want cancer cell to die, we stimulate the death pathway.
if
: we want degenerating neurons survive, we can prevent the apoptosis to
: happen."
:
:
:
--
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 136.152.]
发信人: royluo ( 罗马情结), 信区: Biology
标 题: Re: Apoptosis---Re: Call for MCBJC dicussion
发信站: The unknown SPACE (Tue Apr 1 17:44:39 2003), 站内信件
感觉王晓东已经到颠峰了，细胞凋亡研究也快到尽头了。加入他的组，不等
于是炒剩饭嘛。而且他实验室的技术实在是太生化了，比较窄。
【 在 sianna (交流) 的大作中提到: 】
: 王晓东在国内太有名了，大家感觉如果去他的实验室做postdoc怎么样？
: 【 在 assasin (冷血---何时能被加热？) 的大作中提到: 】
: : This paper published by Wang Xiaodong's lab is a real landmark paper, again.
: : It combines chemical screening with beautiful biochemistry to set up an assay
: : for identifying new factors in apoptotic pathway. They identified 4 factors
: : and characterized one's function. I hope people read this paper and think
: : about the logic and beauty of their way of asking, addressing, explaining
: : scientific questions. I predict that 2 or 3 CNS papers will come out the wang
: : lab following this paper.
: : pathway
: : if
--
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 129.49.]
发信人: justacode (Hi), 信区: Biology
标 题: Re: Call for MCBJC pathway,Mar. 31/done
发信站: The unknown SPACE (Wed Apr 2 11:25:12 2003) WWW-POST
Small molecules screening in search for their functions
within cellular pathways---- chemical genetics----yields information about
other pathway components.
【 在 gardenia (独身主义者) 的大作中提到: 】
: can you send me this article?
: [email protected]
:
: 【 在 justacode (Hi) 的大作中提到: 】
: : Science (2003) 299: 223-226
: : “These caspases cleave many intracellular substrates, ultimately leading
to
: : cell death.”
: : Why pathway study is important?
: : "it's importmant for sure. without knowing the central death pathway, how
: : would people study the regulation of the pathway? Usually signalling
pathway
: : are
: : conserved between species, so if we know the pathway, we can manipulate
: : apoptosis. if we want cancer cell to die, we stimulate the death pathway.
if
: : we want degenerating neurons survive, we can prevent the apoptosis to
: : happen."
:
:
--
※ 修改:·justacode 於 Apr 2 11:25:12 修改本文·[FROM: 140.251.]
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 140.251.]
发信人: Marble (小石头哥哥), 信区: Biology
标 题: Re: Apoptosis---Re: Call for MCBJC dicussion
发信站: The unknown SPACE (Wed Apr 2 00:34:49 2003) WWW-POST
his background determines that he is really an expert in biochemical study of
the cell death pathways. same as roy, my feeling is that mechanistic
investigation of apoptosis is falling into a valley, while the current work is
to sharpen our knowledge by finding more molecules involved in this pathway.
however, cancer or neurodegenerative disease associated cell death would be a
rather more interesting topic, at least for me right now. Wang is a very
productive HHMI, yet i think that postdocs from his lab have to face very
strong competition from him.
meanwhile, if i have to choose a lab for postdoc, i prefer to get into a lab
with very strong bgnd in genetics. while the nematode genome is sequenced and
being analyzed, and the RNAi technique is more frequently used to identify
mutations involved in signalling pathways for different research areas, i
think the mouse-worm combination will be "invincible" in the future, don't you
think so:)?
haven't read these papers carefully though, discuss them later.
【 在 royluo ( 罗马情结) 的大作中提到: 】
:
: 感觉王晓东已经到颠峰了，细胞凋亡研究也快到尽头了。加入他的组，不等
: 于是炒剩饭嘛。而且他实验室的技术实在是太生化了，比较窄。
:
:
: 【 在 sianna (交流) 的大作中提到: 】
: : 王晓东在国内太有名了，大家感觉如果去他的实验室做postdoc怎么样？
: : 【 在 assasin (冷血---何时能被加热？) 的大作中提到: 】
: : : This paper published by Wang Xiaodong's lab is a real landmark paper,
again.
: : : It combines chemical screening with beautiful biochemistry to set up an
assay
: : : for identifying new factors in apoptotic pathway. They identified 4
factors
: : : and characterized one's function. I hope people read this paper and
think
: : : about the logic and beauty of their way of asking, addressing,
explaining
: : : scientific questions. I predict that 2 or 3 CNS papers will come out the
wang
: : : lab following this paper.
: : : pathway
: : : if
:
:
--
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 130.203.]
发信人: justacode (Hi), 信区: Biology
标 题: Re: Apoptosis---Re: Call for MCBJC dicus
发信站: The unknown SPACE (Wed Apr 2 11:32:52 2003) WWW-POST
"Small molecules screening in search for their functions
within cellular pathways---- chemical genetics----yields information about
other pathway components", which is going to be a common method with many
practical applications, not limited to cell death pathways...
BTW, BNU's biochem has close association with chemistry, when Wang was in.
【 在 Marble (小石头哥哥) 的大作中提到: 】
: his background determines that he is really an expert in biochemical study
of
: the cell death pathways. same as roy, my feeling is that mechanistic
: investigation of apoptosis is falling into a valley, while the current work
is
: to sharpen our knowledge by finding more molecules involved in this pathway.
: however, cancer or neurodegenerative disease associated cell death would be
a
: rather more interesting topic, at least for me right now. Wang is a very
: productive HHMI, yet i think that postdocs from his lab have to face very
: strong competition from him.
:
: meanwhile, if i have to choose a lab for postdoc, i prefer to get into a lab
: with very strong bgnd in genetics. while the nematode genome is sequenced
and
: being analyzed, and the RNAi technique is more frequently used to identify
: mutations involved in signalling pathways for different research areas, i
: think the mouse-worm combination will be "invincible" in the future, don't
you
: think so:)?
:
: haven't read these papers carefully though, discuss them later.
:
:
:
: 【 在 royluo ( 罗马情结) 的大作中提到: 】
: :
: : 感觉王晓东已经到颠峰了，细胞凋亡研究也快到尽头了。加入他的组，不等
: : 于是炒剩饭嘛。而且他实验室的技术实在是太生化了，比较窄。
: :
: :
: : 【 在 sianna (交流) 的大作中提到: 】
: : : 王晓东在国内太有名了，大家感觉如果去他的实验室做postdoc怎么样？
: : : 【 在 assasin (冷血---何时能被加热？) 的大作中提到: 】
: : : : This paper published by Wang Xiaodong's lab is a real landmark paper,
: again.
: : : : It combines chemical screening with beautiful biochemistry to set up
an
: assay
: : : : for identifying new factors in apoptotic pathway. They identified 4
: factors
: : : : and characterized one's function. I hope people read this paper and
: think
: : : : about the logic and beauty of their way of asking, addressing,
: explaining
: : : : scientific questions. I predict that 2 or 3 CNS papers will come out
the
: wang
: : : : lab following this paper.
: : : : pathway
: : : : if
: :
: :
:
:
--
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 140.251.]
发信人: Marble (小石头哥哥), 信区: Biology
标 题: Re: Apoptosis---Re: Call for MCBJC dicus
发信站: The unknown SPACE (Wed Apr 2 14:40:37 2003), 站内信件
when i talked with some faculty working in the apoptosis research area,
i found that they have begun to screen for chemical molecules from a
huge library consisting hundred thousands of compounds. the most
important thing for them is to find one that may have clinical potential,
while the target is largely unknown. yet this is true for many drugs proved
by FDA; essentially we do not know the working mechanism for many
drugs. it is a rather new approach to me, some shy guy from a small lab.
and i think the most critical part is to establish a functional assay, in which the
readout could be easily analyzed. i really like this idea of "chemical genetics",
and think about the traditional drugs from China that we have used for so
many years to treat some diseases, there might be exciting things hidden.
the story about arsenite in apoptosis of leukemia is ademonstration. and
meanwhile, the new pharmaceutical is focusing on individual genetic
variation and aiming to develop more efficient drugs for a single subject.
there is a short review on Nature 2003 422:341 about drug discovery and
genomics.
【 在 justacode (Hi) 的大作中提到: 】
: "Small molecules screening in search for their functions
: within cellular pathways---- chemical genetics----yields information about
: other pathway components", which is going to be a common method with many
: practical applications, not limited to cell death pathways...
: BTW, BNU's biochem has close association with chemistry, when Wang was in.
--
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 128.118.]
发信人: Marble (小石头哥哥), 信区: Biology
标 题: Re: Apoptosis---Re: Call for MCBJC dicus
发信站: The unknown SPACE (Sat Apr 5 18:17:10 2003) WWW-POST
i have just read the paper and found it is more interesting than i have
expected. they basically took a chemical screening/biochemical analysis
approach to identify novel genes that regulate the activation of caspase-3.
they found a chemical compound, namely PETCM, that could promote apoptosis,
then they fractionated protein extracts and looked for proteins that mediated
the apoptome promotion effect of PETCM; and they characterized several PHAP
genes that are tumor suppressors as well as ProT which is an oncogene. PHAPI
acts as positive regulator for apoptome formation, while ProT is an inhibitor;
and they seem to act at different steps for the apoptome formation.
so my questions are: what are the proteins that interact with PHAPI and ProT
before and after caspase activation? could this be solved by proteomics? since
PETCM releases the suppression effect from Q100 fraction, this question should
be addressed in the absence and presence of PETCM. i do not think that they
only purified one inhibitory factor as the ProT; actually they mentioned that
the PETCM effect could not be reproduced in a reconstituted system with
purified proteins, and additional factors may exist.
very interesting thing is that RNAi for ProT sensitizes HeLa cells to apotosis
after UV irradiation and this probably suggests that RNAi for oncogene in
certain circumstances may have clinical usage. it will be interesting to know
occurrence of mutations of PHAPI and ProT in diseases, particularly in cancers
with abnormal apoptosis. i do not know whether knockout animal models are
available now for these genes, but it seems a little problematic with PHAP due
to redundancy.
as for the chemical compound PETCM, does PETCM bind directly to caspase-3? if
so, what are the binding sites and stoichemistry? would it be possible to
generate missiled-PETCM that target cancerous cells to promote cell death, if
the tocixity is tolerable?
this paper applied a lot of biochemistry and a little bit of genetics. for the
future study, i think a specific structure-oriented chemical compound library
screening should be carried out in a variety of genetic background, and this
requires knowledge of the protein structure as well as key components of the
signalling pathway. and bioinformatic analysis for functional domain and
genetic/biochemical shuffeling experiments may provide invaluable information
as well. as i am very interested in applying genetic approaches to tackle such
problem, i am wondering whether RNAi for mammalian cell and functional assay
could be used to screen genes involved in the signalling pathway. (for
example, in the presence of ATP or PETCM and assay the formation of
apoptosome).
...
...
...
...
thanks for your patience to read my blah blah blah ... hehe.
--
※ 修改:·Marble 於 Apr 5 18:17:10 修改本文·[FROM: 128.118.]
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 128.118.]
发信人: leohawk (leohawk), 信区: Biology
标 题: Re: Apoptosis---Re: Call for MCBJC dicus
发信站: The unknown SPACE (Sat Apr 5 21:45:04 2003) WWW-POST
It is an amazing paper, proof of principle of HTS methods for drug screening
and deciphering
complicated signal transduction network.
However, I don't get it when they say: "In contrast, the presense of PHAPI did
not affect ... and
increased caspase-9 was associated with apoptosome" This should be the natural
function of PHAPI, right? and did they do a timecourse? as to if add PHAPI
first, then
ProT later, will this be reversed? I probably missed something here.
and why they only tested PHAP1, I would be very interested in the other 2,
individual
function and combined function...
ProT might be involved in DNA repair from data they presented, it is probably
involved
in blocking apoptosis to give cell enough time to repair UV damaged DNA ...
hopefully
only to certain level. My wide guess is there is something inhibit ProT
function naturally
occuring in cell, only to be initiated when cell damage is beyond control...
may well
be a feedback loop of the whole caspase pathway...
one door open, release the factor that open all other doors...
only wild guess
【 在 Marble (小石头哥哥) 的大作中提到: 】
: i have just read the paper and found it is more interesting than i have
: expected. they basically took a chemical screening/biochemical analysis
: approach to identify novel genes that regulate the activation of caspase-3.
: they found a chemical compound, namely PETCM, that could promote apoptosis,
: then they fractionated protein extracts and looked for proteins that
mediated
: the apoptome promotion effect of PETCM; and they characterized several PHAP
: genes that are tumor suppressors as well as ProT which is an oncogene. PHAPI
: acts as positive regulator for apoptome formation, while ProT is an
inhibitor;
: and they seem to act at different steps for the apoptome formation.
:
: so my questions are: what are the proteins that interact with PHAPI and ProT
: before and after caspase activation? could this be solved by proteomics?
since
: PETCM releases the suppression effect from Q100 fraction, this question
should
: be addressed in the absence and presence of PETCM. i do not think that they
: only purified one inhibitory factor as the ProT; actually they mentioned
that
: the PETCM effect could not be reproduced in a reconstituted system with
: purified proteins, and additional factors may exist.
:
: very interesting thing is that RNAi for ProT sensitizes HeLa cells to
apotosis
: after UV irradiation and this probably suggests that RNAi for oncogene in
: certain circumstances may have clinical usage. it will be interesting to
know
: occurrence of mutations of PHAPI and ProT in diseases, particularly in
cancers
: with abnormal apoptosis. i do not know whether knockout animal models are
: available now for these genes, but it seems a little problematic with PHAP
due
: to redundancy.
:
: as for the chemical compound PETCM, does PETCM bind directly to caspase-3?
if
: so, what are the binding sites and stoichemistry? would it be possible to
: generate missiled-PETCM that target cancerous cells to promote cell death,
if
: the tocixity is tolerable?
:
: this paper applied a lot of biochemistry and a little bit of genetics. for
the
: future study, i think a specific structure-oriented chemical compound
library
: screening should be carried out in a variety of genetic background, and this
: requires knowledge of the protein structure as well as key components of the
: signalling pathway. and bioinformatic analysis for functional domain and
: genetic/biochemical shuffeling experiments may provide invaluable
information
: as well. as i am very interested in applying genetic approaches to tackle
such
: problem, i am wondering whether RNAi for mammalian cell and functional assay
: could be used to screen genes involved in the signalling pathway. (for
: example, in the presence of ATP or PETCM and assay the formation of
: apoptosome).
:
: ...
: ...
:
:
:
: ...
: ...
--
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 128.6.]
发信人: Marble (小石头哥哥), 信区: Biology
标 题: Re: Apoptosis---Re: Call for MCBJC dicus
发信站: The unknown SPACE (Mon Apr 7 15:05:58 2003), 站内信件
i think in Fig 4C, they used APAF-1 western blot to address
the formation of apoptosome (consists of Apaf-1 and cyt c),
which is necessary to activation of downstream caspase-9.
PHAPI did not increase apoptosome formation, yet it enhanced
activation of caspase-9 to promote cell death. in contrast,
ProT inhibited formation of apoptosome, which could be released
by the chemical PETCM. and they proposed that PHAPI and ProT
act on different steps during apoptosis. not really sure about
the other PHAPs, maybe PHAPI has been mostly studied and more
pubmed references are available. i did not read the referrences.
【 在 leohawk (leohawk) 的大作中提到: 】
: It is an amazing paper, proof of principle of HTS methods for drug screening
: and deciphering
: complicated signal transduction network.
: However, I don't get it when they say: "In contrast, the presense of PHAPI did
: not affect ... and
: increased caspase-9 was associated with apoptosome" This should be the natural
: function of PHAPI, right? and did they do a timecourse? as to if add PHAPI
: first, then
: ProT later, will this be reversed? I probably missed something here.
: and why they only tested PHAP1, I would be very interested in the other 2,
: individual
: function and combined function...
: ProT might be involved in DNA repair from data they presented, it is probably
: involved
: in blocking apoptosis to give cell enough time to repair UV damaged DNA ...
: hopefully
: only to certain level. My wide guess is there is something inhibit ProT
: function naturally
: occuring in cell, only to be initiated when cell damage is beyond control...
: may well
: be a feedback loop of the whole caspase pathway...
: one door open, release the factor that open all other doors...
: only wild guess
--
※ 来源:．The unknown SPACE bbs.mit.edu．[FROM: 128.118.]
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