Linkage between melanocytic tumor development and early burst of Ret protein expression for tolerance induction in metallothionein-I/ret transgenic mouse lines

Kato, Masashi; Liu, Wei; Akhand, Anwarul A.; Dai, Yan; Ohbayashi, Masaharu; Tuzuki, Toyonori; Suzuki, Haruhiko; Isobe, K; Takahashi, Masahide; Nakashima, Izumi

doi:10.1038/sj.onc.1202329

Cited by 34 publications

(40 citation statements)

References 15 publications

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“…Based on the results obtained, we would propose that UV also affects proteins as oncogene products for superactivation, which might be involved in the mechanism of stepwise oncogenesis. Partially supporting this view, we have observed that repeated UV irradiation of otherwise benign melanocytic tumors developed in RETtransgenic mice (Iwamoto et al, 1991;Kato et al, 1999) induced their malignant transformation, accompanying extensive superactivation of Ret (our unpublished results), although the exact cause-and-effect relation of these two events remains to be proved.…”

Section: Discussionmentioning

confidence: 54%

Ultraviolet Light Induces Redox Reaction–mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

Kato¹,

Iwashita

Takeda³

et al. 2000

MBoC

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The c-RET proto-oncogene encodes a receptor-type tyrosine kinase, and its mutations in the germ line are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B). Ret kinases are constitutively activated as a result of MEN2A mutations (Ret-MEN2A) or MEN2B mutations (Ret-MEN2B). Here we demonstrate that UV light (UV) irradiation induces superactivation of the constitutively activated Ret-MEN2A and Ret-MEN2B as well as activation of c-Ret. Before UV irradiation, small percentages of c-Ret (3-4%) and Ret-MEN2B (1-2%) and large percentages of Ret-MEN2A (30 -40%) were dimerized through disulfide bonds. These dimerized Ret proteins were preferentially autophosphorylated, suggesting a close relation between up-regulated kinase activity and disulfide bond-mediated dimerization of Ret proteins. We found that UV irradiation promotes the disulfide bond-mediated dimerization of the Ret proteins, in close association with activation and superactivation of Ret kinases. UV irradiation also induced dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Interestingly, the levels of basic kinase activity and dimerization of Ret-PTC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-PTC-1 was replaced by alanine, were low and were not increased by UV irradiation. These results suggest that Ret-PTC-1 cysteine 376 is one of possibly multiple critical target amino acids of UV for Ret kinase activation. Overexpression of Cu/Zn superoxide dismutase in cells as a result of gene transfection prevented both the UVmediated promotion of dimerization and the superactivation of Ret-MEN2A kinase. These results suggest that the UV-induced free radicals in cells attack intracellular domains of Ret to dimerize the kinase proteins for superactivation.

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Section: Discussionmentioning

confidence: 54%

Ultraviolet Light Induces Redox Reaction–mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

Kato¹,

Iwashita

Takeda³

et al. 2000

MBoC

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“…Due to the transport of MT out of the cells, its level is significantly reduced in intracellular space. With respect to the MT relation to zinc ions, whose metabolism is abnormal in the prostate tumor tissue, MT participation on pathogenesis of malignant disorder can be expected [45][46][47][48][49][50][51][52][53]. To date, there is no evidence in the literature determining metallothionein level in 22Rv1 and PNT1A cell lines, however, there were done some experiments describing behaviour of RWPE-1 cell line, which revealed similarities of behaviour of this cell line with prostate tissue [54] as well as in the case of PC-3 cell line [55].…”

Section: Discussionmentioning

confidence: 99%

Evaluation ofalpha-methylacyl-CoA racemase, metallothionein and prostate specific antigen as prostate cancer prognostic markers

Gumulec¹,

Masařík²,

Křížková³

et al. 2012

neo

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Current diagnostic techniques are inefficient in distinguishing latent and low-risk forms of prostate cancer from high-risk forms. The present study is focused on determination of putative tumor markers of aggressive high-grade forms of prostate cancer. Potential markers were determined in blood sera of 133 patients (82 cases and 51 controls) and in cell lines (Gleason score 9-derived 22Rv1 and normal tissue derived PNT1A) on mRNA and protein levels. Alpha-methylacyl-CoA racemase (AMACR), metallothionein classes 1A and 2A (MT1A and MT2A) were determined and compared to prostate specific antigen (PSA) levels. On mRNA level, significantly increased expression of MT2A (2.4-fold), PSA (2.6-fold) and AMACR (8.4-fold) and insignificantly (1.9-fold) elevated MT1A in 22Rv1 compared to non-tumor PNT1A were determined. On protein level, significant enhancement of free PSA and total PSA in tumor cell line was evident. AMACR protein was 1.5-fold elevated in tumor line (below the level of significance). Contrary to mRNA, significantly (p = 0.01) reduced level of MT protein in tumor lines was determined. In the case of serum level, significantly enhanced MT level (4.5-fold) in patients' sera was found. No significant changes were observed in the case of AMACR. These findings indicate possible alternative role of MT to PSA prostate cancer marker. In addition, level of AMACR is distinctly higher in the Gleason score 9 in serum of patients and MT shows a descending trend in relation to Gleason score.

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“…After the membranes had been reacted with the anti-Ret (reactive to both c-Ret and RFP-RET; Immuno-Biological laboratories, Gunma, Japan) antibody, the reaction was examined using Western Blot Chemiluminescence Reagent (DuPont NEN, Boston, MA, USA). Immunoprecipitation and immunohistochemistry with antiRet antibody (Kato et al, 1999(Kato et al, , 2000 or anti-S-100 protein (Iwamoto et al, 1991) were performed as described previously.…”

Section: Immunoblot Immunoprecipitation and Immunohistochemistrymentioning

confidence: 99%

“…Previously, we established four transgenic mouse lines (line 192, line 242, line 304 and line 319) by introducing the RFP-RET oncogene, fused to the mouse metallothionein-l promoter-enhancer (Iwamoto et al, 1991;Kato et al, 1998bKato et al, , 1999 for a broad spectrum of expression, which encodes an activated form of RET kinase. The genetic background of the original RFP-RET-transgenic mice was F1 of C57BL/6 and BALB/c strains (Iwamoto et al, 1991).…”

Section: Preparation Of Micementioning

confidence: 99%

“…Previously, we established four transgenic mouse lines that constitutively activated RET (RFP-RET) and incidentally found that extensive skin melanosis spontaneously developed in these transgenic mouse lines (Iwamoto et al, 1991;Kato et al, 1998bKato et al, , 1999. This unexpected observation suggested that the RET kinase plays a role in melanin production in the skin.…”

Section: Introductionmentioning

confidence: 99%

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RET tyrosine kinase enhances hair growth in association with promotion of melanogenesis

et al. 2001

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We ®rst demonstrated that c-Ret protein is transiently expressed mainly in the inner and outer root sheaths of hair follicles soon after birth in the skin of normal C57BL/6 and BALB/c mice. A longer-lasting expression of activated RET protein overlapped the c-Ret expression with some preferential expression in the outer root sheath in close association with increase in the number of S-100 protein-containing cells in the area and excess melanogenesis in and around hair bulbs in the skin of RFP-RET-transgenic mice on a C57BL/6 background (RFP-RET/B6). Hair follicles in the skin of the transgenic mice continuously showed histology of the anagen phase, and the recovery period for the hair of the transgenic mice after shaving was shortened. Such growth promotion was not observed in the case of white hairs of RFP-RET-transgenic mice on a BALB/c background. These results suggest that RET works to extend the anagen phase in association with upregulation of melanin production. Oncogene (2001) 20, 7536 ± 7541.

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Linkage between melanocytic tumor development and early burst of Ret protein expression for tolerance induction in metallothionein-I/ret transgenic mouse lines

Cited by 34 publications

References 15 publications

Ultraviolet Light Induces Redox Reaction–mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

Ultraviolet Light Induces Redox Reaction–mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

Evaluation ofalpha-methylacyl-CoA racemase, metallothionein and prostate specific antigen as prostate cancer prognostic markers

RET tyrosine kinase enhances hair growth in association with promotion of melanogenesis

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