Loss of VHL promotes progerin expression, leading to impaired p14/ARF function and suppression of p53 activity.
Renal cell carcinomas (RCCs) are frequently occurring genitourinary malignancies in the aged population. A morphological characteristic of RCCs is an irregular nuclear shape, which is used to index cancer grades. Other features of RCCs include the genetic inactivation of the von Hippel-Lindau gene, VHL, and p53 genetic-independent inactivation. An aberrant nuclear shape or p53 suppression has not yet been demonstrated. We examined the effect of progerin (an altered splicing product of the LMNA gene linked to Hutchinson Gilford progeria syndrome; HGPS) on the nuclear deformation of RCCs in comparison to that of HGPS cells. In this study, we showed that progerin was suppressed by pVHL and was responsible for nuclear irregularities as well as p53 inactivation. Thus, progerin suppression can ameliorate nuclear abnormalities and reactivate p53 in response to genotoxic addition. Furthermore, we found that progerin was a target of pVHL E3 ligase and suppressed p53 activity by p14/ARF inhibition. Our findings indicate that the elevated expression of progerin in RCCs results from the loss of pVHL and leads to p53 inactivation through p14/ARF suppression. Interestingly, we showed that progerin was expressed in human leukemia and primary cell lines, raising the possibility that the expression of this LMNA variant may be a common event in age-related cancer progression.
Department of Molecular Biology; College of Natural Science, Pusan National University; Busan, Republic of Korea.
Youn-Sang
YS
Jung
Su-Jin
SJ
Lee
Sun-Hye
SH
Lee
Ji-Yun
JY
Chung
Youn Jin
YJ
Jung
Sang Hyun
SH
Hwang
Nam-Chul
NC
Ha
Bum-Joon
BJ
Park
D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000648:ultrastructure; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034904:Lamin Type A; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D053140:Organelle Shape / Q000235:genetics; D061251:Primary Cell Culture; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C090764:prelamin A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human