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Disorders associated with G protein- coupled receptors -Kaposi

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Title: Somatic mutation Author: aLong Last modified by: lib Created Date: 12/5/2006 7:35:07 AM Document presentation format: Company – PowerPoint PPT presentation

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Title: Disorders associated with G protein- coupled receptors -Kaposi


1
Disorders associated with G protein- coupled
receptors-Kaposis sarcoma (????? )
  • ???

  • 1040800114

2
  • ???????????
  • ?????????????
  • ????????

3
?????
  • ????????????,?????????????,??????????????
  • ??????????????,??????????????????????????????,????
    ????????????
  • ????????Kaposi(???)1872???

4
????
  • ????????,????????????????????????????????,????????
    ,?????,?????????????????????????
  • ?????????????????????????????(??)??????(??)?

5
  • ??????????
  • ???????
  • ???
  • ????
  • ???????????

6
???????
  • ???,????,???????
  • ??
  • ????????????????????

7
???(???Kaposi??)
  • ???????,?????13-171,??????Kaposi?????????????
    ???5-8????,???????????

8
????(AIDS??Kaposi??)
  • ????????????????,?????1061(why?),HIV???????Kapo
    si????????????20,000?????????17??
  • ????????????????????????????????????????,???????
    ?????????????????????,??????????????????????????,?
    ????????

9
???????????(?????)
  • ???????????????,???20-60?,??????,????????????????
    ?????

10
Kaposis sarcoma-associated herpesvirus(?????8? )
  • In 1994, the Kaposis sarcoma-associated
    herpesvirus (KSHV/HHV-8) was identified as the
    etiologic agent (??????? )of Kaposis sarcoma
    (KS).
  • which gene contributes to the initiation of
    KS ?

11
latent genes blue lytic genes red
12
  • Latent genes are expressed in almost all spindle
    cells in late KS lesions
  • Lytic genes are expressed during the phase of the
    viral life cycle when viral progeny are produced
    .these viral genes are expressed in cells
    ultimately destined to die (lyse)

13
KSHV vGPCR responsible for the initiation of KS
  • evidence
  • when a KS model in which endothelial-specific
    retroviral transduction was used, vGPCR produced
    vascular tumors in mice
  • two transgenic animals that express vGPCR under
    either a ubiquitous (SV40) promoter or a T
    cell-specific promoter only manifest vascular
    tumors

14
  • HHV-8?ORE74?????G???????,???????(??????)??,???????
    ?????????,???????????,????????????????????????????
    ?,???????
  • ????????????????,???????????????KSHV?????????????

15
??????
hHV-8?ORF74
??
G???????
??
?????????????
Aborted lytic cycle progression
HIV-1 Tat. inflammation
?????????
16
?????????
????????
??????
17
  • The KSHV vGPCR is a member of the family of CXC
    chemokine G-protein-linked receptors.this
    receptor exhibits ligand-independent activities .
  • activation of the serine-threonine kinase Akt by
    vGPCR may represent a critical intracellular
    pathway in the blockade of cell death

18
  • vGPCR induces the secretion of angiogenic growth
    factors from expressing cells, including VEGF,
    IL-8, and Gro- suggesting that vGPCR may serve a
    role both in direct cell transformation and
    indirect (paracrine) cell transformation

19
Mechanisms control vGPCR
  • 1) vGPCR is transcribed within the 3' end of
    a bicistronic mRNA, thus restricting its
    expression
  • 2) Host cytokines (e.g., SDF-1 , IP-10) act
    as antagonists to vGPCR signaling

20
  • 3) KSHV itself encodes a lytic gene, vMIP2, whose
    protein product acts as an antagonist to vGPCR
    signaling
  • 4)As mentioned above, as a lytic gene, vGPCR is
    expressed in cells ultimately destined to die.

21
  • Proliferative signals initiated by vGPCR prolong
    lytic cell survival to ensure efficient viral
    replication.
  • proangiogenic growth factors secreted by
    vGPCR-expressing cells recruit neighboring
    endothelial cells that are then infected by the
    newly formed progeny virion.

22
  • How can vGPCR be responsible for the initiation
    of KS tumors if its expression and signaling are
    so tightly controlled ?

23
  • under special circumstances (e.g., HIV
    co-infection, inflammation, aborted lytic cycle
    progression), dysregulation of the normal viral
    program may result in nonlytic expression and
    enhanced signaling of vGPCR, ultimately
    manifesting as KS.

24
  • 1) HIV Tat increases expression of KSHV lytic
    genes, including vGPCR, whose expression is
    significantly enhanced in aggressive AIDS-KS as
    compared with the more benign classical KS
    lesions
  • 2) Several inflammatory cytokines released by HIV
    infected cells can increase vGPCR signaling

25
  • The critical role for these locally released
    inflammatory cytokines for vGPCR oncogenesis was
    recently confirmed by a transgenic animal
    encoding a mutant vGPCR lacking a ligand binding
    domain that failed to manifest tumors despite its
    constitutive activity

26
(No Transcript)
27
KS??
  • (1)????
  • ? ????(Vinblastine)?AIDS?KS?????,????4mg,?????5??
    ?20-30ml????,???????2.5-3109/L????,?????9mg,????,
    6-8??
  • ? ???(Vincristine)???????,?AIDS?KS?????,1.4-2.0mg/
    ?,?????20-30ml????,?????

28
  • ? ????(etoposide vepesid)???AIDS??????
  • ? ????,????
  • (2)????,?????,????1800-3000rad?
  • (3)??????
  • (4)????????????????????????
  • (5)vGPCR ?????

29
thank you
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