Jing LiFollow

Date of Award

2008

Degree Name

Biological Sciences

College

College of Science

Type of Degree

M.S.

Document Type

Thesis

First Advisor

Simon Collier

Second Advisor

Maiyon Park

Third Advisor

Guozhang Zhu

Abstract

Chmp1A (Chromatin modifying protein 1A/Charged multivesicular protein 1A) is a member of the ESCRT-III (Endosomal Sorting Complex Required for Transport) family, which mediates trafficking via MVB (multivesicular body) formation and sorting. Our studies suggest that Chmp1A is a novel tumor suppressor, especially in the pancreas. Knockdown of Chmp1A resulted in an increase of anchorage-independent growth of HEK 293T cells. Moreover, we showed that Chmp1A depleted HEK 293T cells forms tumor in xenograft mice. Knockdown of Chmp1A in PanC-1 cells promoted cell growth. In contrast, Doxycycline induced over-expression of Chmp1A in pancreatic cancer cells (PanC-1) resulted in cell growth inhibition, tumor xenograft inhibitions, and increased protein level of pan-P53, phospho-P53, and cellular retinol-binding protein 1 (CRBP-1). CRBP-1 is a key regulator of All-trans retinoic acid (ATRA) signaling. ATRA and its derivatives play a critical role in regulating cell proliferation. Chmp1A positively regulated CRBP-1. To investigate the specific role of Chmp1A in ATRA signaling, ATRA responsive and non-responsive pancreatic tumor cells were treated with ATRA in vitro. The growth inhibition of ATRA was confirmed by growth assay. In the ATRA responsive cell line, ATRA treatment apparently increased the expression of Chmp1A, CRBP-1, phospho-P53 and pan-P53. ATRA also facilitated translocation of Chmp1A into the nucleus. The knockdown of Chmp1A abolished the growth inhibition of ATRA on pancreatic cancer cells. Collectively, our data indicate that Chmp1A acts as a novel tumor suppressor by regulating P53 and is indispensable for anti-proliferative action of ATRA in pancreatic cancer cells by regulating CRBP-1.

Subject

Proteins - Research

Subject

Pancreas - Cancer - Research

Subject

Stem cells - Research

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