Rudolph博士来研究访问并举办学术讲座,博士应邀访问研究所并举办学术讲座

Abstract:

For many years we have investigated the basic mechanisms of
transformation of normal cells into cancer cells and the resistance of
cancer cells to targeted drugs .More specifically, our research has
focused on 1) understanding how cancer cells hijack clathrin trafficking
pathways to increase signals from multiple growth factor receptors in
parallel (Rao et al., Cancer Cell 2003; 3:471) and 2) understanding how
tyrosine kinase oncogene induced cancers resist targeted therapiesin
vivo
(Oravecz-wilson et al, Cancer Cell 2009; 16:137). In my talk I will
touch on how the clathrin binding protein Huntingtin Interacting Protein
1 has been implicated in tumorigenesis and normal cell physiology.We
have found that HIP1 is elevated in many cancers and have evaluated the
clinical implications of this in prostate cancer patients and found that
HIP1 expression is a strong marker of tumor progression.We have shown
that HIP1’s expression is necessary for some normal and cancer cells to
survive in vivo and that it directly transforms fibroblasts as a result
of altered levels of multiple growth factor receptors.In addition HIP1
knockout mice have a general “cell loss” or degenerative phenotype as
evidenced by hematopoietic defects, testicular degeneration, spinal
defects, diminished prostate tumorigenesis and cataracts.The putative
regulation of endocytic pathways by HIP1 and HIP1r could explain our
observations.I.e. alteration of these pathways may be the reason for the
altered growth characteristics during overexpression or knockout of HIP1
and HIP1r.Because it was originally linked to neoplasia by our discovery
of the oncogenic HIP1/PDGFβR fusion protein that resulted from a t
chromosomal translocation in a patient with leukemia, I will also
discuss our work towards a better understanding the transforming biology
of HIP1/PDGFβR and other tyrosine kinase oncogenes that cause chronic
leukemias.We have generated and are analyzing HIP1/PDGFβR and Bcr/Abl
conditional knock-in mice.Using these “high-end” mouse models we are in
a unique position to define common pathways of leukemogenesis by fusion
tyrosine kinases in vivo.These knock-in mice are being used to
rigorously test the tumorigenic stem cell hypothesis in the setting of
realistic expression of human oncogenes, to understand mechanisms of
transformation by HIP1/PDGFβR and Bcr/Abl and to make sense of
therapeutic resistance to tyrosine kinase inhibitors (e.g. imatinib,
nilotinib and desatinib) or further downstream signal transduction
pathway inhibitors .In sum, much of the laboratory focus is to
understand the necessary role of the HIP1 family in modulation of
fundamental cellular pathways in the biology of normal and neoplastic
cells.

Apoptosis

图片 1

Abstract:

Adarotene causes a dose-dependent growth inhibition in a large panel of
human tumor cell lines with IC50ranging from 0.1 to 0.3 μM. Adarotene
causes cell accumulation in G1/S or S phase of cell cycle depending on
tumor cells IGROV-1 and
DU145[1];).
Adarotene is apoptotic and cytotoxic on a large spectrum of cancerous
and leukemic cells, including freshly isolated AML blasts in primary
culture. The molecular target of ST1926 apoptotic activity in myeloid
leukemia cells is similar to the ligand-binding domain of RARγ.
Adarotene treatment of cells results in rapid accumulation of
intracellular
calcium[2];).

2009年11月16日,德国乌尔姆大学分子医学系和克朗普干细胞老化研究组主任Karl
L. Rudolph博士来研究访问并举办学术讲座。讲座题目为:Telomere
dysfunction, DNA damage checkpoints, and aging。袭荣文博士主持讲座。

2012年2月21日,美国得克萨斯大学西南医学院内科教授Theodora S.
Ross博士应邀访问研究所并举办学术讲座。讲座的题目为:Tyrosine Kinases,
Cancer and their Connection to HIP1。陈良博士主持讲座。

相关产品

As a central component in telomere dysfunction induced DNA damage
pathways, p53 deletion meliorated the germ line stem cells intrinsic
defects. However, the longevity of p53-/- Terc-/- mice was reduced due
to the early onset of tumour incidence and accumulation of DNA damage in
stem cells. Deletion of p21, the downstream senescence checkpoint of
p53, improved the life span of telomere dysfunctional mice without
promoting cancer formation. Exo1 deletion improved maintenance of
intestinal epithelia, and prolonged lifespan of late generation
telomerase knockout mice. Exo1-deletion prevented the initiation H2AX)
and activation of downstream DNA-damage signalsgof DNA damage signals in
intestinal crypts. The deletion of Exo1 partially rescued cell cycle
arrest and apoptosis of intestinal progenitor cells but did not
accelerate the incidence of spontaneous cancer formation in aging
telomere dysfunctional mice. In addition to the stem cell intrinsic
defects,telomere dysfunction also provokes defects of the hematopoietic
environment that impair B-lymphopoiesis but increase myeloid
proliferation in aging telomerase knockout mice. Moreover, the
dysfunctional environment limited the engraftment of transplanted
wildtype HSCs. Dysfunction of the hematopoietic environment increased
during aging of mTERC-/- mice and was associated with progressive
telomere shortening in bone marrow stromal cells.

图片 2

Cisplatin-Epibrassinolide-Elesclomol-Betulinic
acid-Myricetin-Apoptosis
Activator
2-Betulin-Cholesterol
myristate-NSC348884-SMIP004-Taurochenodeoxycholic
acid-(E)-[6]-Dehydroparadol-Baohuoside
I-Bisdemethoxycurcumin-Columbianadin-

Telomere has been known as a mitotic clock that controls cellular
ageing. Independent lines of evidence indicate that telomere dysfunction
induces both cell intrinsic checkpoints and cell extrinsic checkpoint
leading to an age-associated stem cell dysfunction. Genetically modified
mouse lacking telomerase activity delivered an invaluable model for
probing the in vivo consequences of replicative senescence and
telomere-based stem cell ageing.Dysfunctional telomeres induce a DNA
damage response leading to cell cycle arrest or apoptosis.Disturb genes
regulating DNA damage checkpoints in response to telomere dysfunction
partially rescued the degenerative phenotypes and adult stem cell
ageing, but in some cases increased tumorigenesis.

“目录号: HY-14808

Description

[2].Garattini E, et al. ST1926, a novel and orally active
retinoid-related molecule inducing apoptosis in myeloid leukemia cells:
modulation of intracellular calcium homeostasis. Blood. 2004 Jan
1;103(1):194-207.

References

In Vitro

Adarotene is an effective apoptosis inducer, which surprisingly produces
DNA damage and exhibites a potent antiproliferative activity on a large
panel of human tumor cells.

Adarotene (15, 20 mg/kg, p.o.) causes a significant tumor growth
inhibition in a human ovarian carcinoma, A2780/DX, and in a human
melanoma, MeWo, growing in nude
mice[1];).
Adarotene (30, 40 mg/kg, p.o.) results in a significant and
dose-dependent increase in the life span of NB4-bearing SCID mice
without overt
toxicity[2];).

Apoptosis-

生物活性

In Vivo

[1].Cincinelli R, et al. A novel atypical retinoid endowed with
proapoptotic and antitumor activity. J Med Chem. 2003 Mar
13;46(6):909-12.

Adarotene 是一种有效的apoptosis诱导剂,通过产生 DNA
损伤,来阻止人类肿瘤细胞的增殖。

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